Non-peptidic npy y2 receptor inhibitors

ABSTRACT

The invention provides novel non-peptidic NPY Y2 receptor inhibitors useful in treating or preventing: anxiolytic disorders or depression; injured mammalian nerve tissue; conditions responsive to treatment through administration of a neurotrophic factor; neurological disorders; bone loss; substance related disorders; obesity; or an obesity-related disorder. Compounds of the invention are also useful in modulating endocrine functions, particularly endocrine functions controlled by the pituitary and hypothalamic glands, and are therefore useful in the treatment or prevention of inovulation and infertility.

FIELD OF THE INVENTION

The invention provides novel non-peptidic NPY Y2 receptor inhibitorsuseful in treating or preventing: anxiolytic disorders and depression;injured mammalian nerve tissue; a condition responsive to treatmentthrough administration of a neurotrophic factor; a neurologicaldisorder; bone loss; substance related disorders; obesity; or anobesity-related disorder. Compounds of the invention are also useful inmodulating endocrine functions; particularly endocrine functionscontrolled by the pituitary and hypothalamic glands, and may be used totreat inovulation and infertility.

BACKGROUND OF THE INVENTION

Regulation and function of the mammalian central nervous system isgoverned by a series of interdependent receptors, neurons,neurotransmitters, and proteins. The neurons play a vital role in thissystem, for when externally or internally stimulated, they react byreleasing neurotransmitters that bind to specific proteins. Commonexamples of endogenous small molecule neurotransmitters such asacetylcholine, adrenaline, norepinephrine, dopamine, serotonin,glutamate, and gamma-aminobutyric acid are well known, as are thespecific receptors that recognize these compounds as ligands (“TheBiochemical Basis of Neuropharmacology”, Sixth Edition, Cooper, J. R.;Bloom, F. E.; Roth, R. H. Eds., Oxford University Press, New York, N.Y.1991).

In addition to the endogenous small molecule neurotransmitters, there isincreasing evidence that neuropeptides play an integral role in neuronaloperations. Neuropeptides are now believed to be co-localized withperhaps more than one-half of the 100 billion neurons of the humancentral nervous system. In addition to being found in humans,neuropeptides have been discovered in a number of animal species. Insome instances, the composition of these peptides is remarkablyhomogenous among species. This finding suggests that the function ofneuropeptides is vital and has been impervious to evolutionary changes.Furthermore, neuropeptides, unlike small molecule neurotransmitters, aretypically synthesized by the neuronal ribosome. In some cases, theactive neuropeptides are produced as part of a larger protein that isenzymatically processed to yield the active substance. Based upon thesedifferences, compared to small molecule neurotransmitters,neuropeptide-based strategies may offer novel therapies for thetreatment of CNS diseases and disorders. Specifically, agents thataffect the binding of neuropeptides to their respective receptors orameliorate responses that are mediated by neuropeptides are potentialtherapies for diseases associated with neuropeptides.

There are a number of afflictions that are associated with the complexinterdependent system of receptors and ligands within the centralnervous system; these include neurodegenerative diseases, affectivedisorders such as anxiety, depression, pain and schizophrenia, andaffective conditions that include a metabolic component, namely obesity.Such conditions, disorders, and diseases have been treated with smallmolecules and peptides that modulate neuronal responses to endogenousneurotransmitters.

One example of this class of neuropeptides is neuropeptide Y (NPY). NPYwas first isolated from porcine brain (Tatemoto, K. et al. Nature 1982,296, 659) and was shown to be structurally similar to other members ofthe pancreatic polypeptide (PP) family such as peptide YY, which isprimarily synthesized by endocrine cells in the gut, and pancreaticpolypeptide, which is synthesized by the pancreas. NPY is a singlepeptide protein that consists of thirty-six amino acids containing anamidated C-terminus. Like other members of the pancreatic polypeptidefamily, NPY has a distinctive conformation that consists of anN-terminal polyproline helical region and an amphiphilic alpha-helixjoined by a characteristic PP-fold (Vladimir, S. et al. Biochemistry1990, 20, 4509). Furthermore, NPY sequences from a number of animalspecies have been elucidated and all show a high degree of amino acidhomology to the human protein (more than 94% in rat, dog, rabbit, pig,cow, sheep) (see Larhammar, D. in “The Biology of Neuropeptide Y andRelated Peptides”, Colmers, W. F. and Wahlestedt, C. Eds., Humana Press,Totowa, N.J. 1993).

Endogenous receptor proteins that bind NPY and related peptides asligands have been identified and distinguished, and several suchproteins have been cloned and expressed. Six different receptor subtypes[Y1, Y2, Y3, Y4 (PP), Y5, Y6 (formerly designated as a Y5 receptor)] arerecognized today based upon binding profile, pharmacology, and/orcomposition if identity is known (Wahlestedt, C. et al. Ann. N.Y. Acad.Sci. 1990, 611, 7; Larhammar, D. et al. J. Biol. Chem. 1992, 267, 10935;Wahlestedt, C. et al. Regul. Pept. 1986, 13, 307; Fuhlendorff, J. U. etal. Proc. Natl. Acad. Sci. U.S.A. 1990, 87, 182; Grundemar, L. et al. J.Pharmacol. Exp. Ther. 1991, 258, 633; Laburthe, M. et al. Endocrinology1986, 118, 1910; Castan, I. et al. Endocrinology 1992, 131, 1970;Gerald, C. et al. Nature 1996, 382, 168; Weinberg, D. H. et al. J. Biol.Chem. 1996, 271, 16435; Gehlert, D. et al. Curr. Pharm. Des. 1995, 1,295; Lundberg, J. M. et al. Trends in Pharmacological Sciences 1996, 17,301). Most and perhaps all NPY receptor proteins belong to the family ofso-called G-protein coupled receptors (GPCRs). The neuropeptide Y5receptor, a putative GPCR, is negatively coupled to cellular cyclicadenosine monophosphate (cAMP) levels via the action of adenylatecyclase (Gerald, C. et al. Nature 1996, 382, 168; Gerald, C. et al. PCTWO 96/16542). For example, NPY inhibits forskolin-stimulated cAMPproduction/levels in a neuroblastoma cell line. A Y5 ligand that mimicsNPY in this fashion is an agonist whereas one that competitivelyreverses the NPY inhibition of forskolin-stimulated cAMP production isan antagonist.

The neuropeptide Y2 receptor has high affinity for NPY and PYY, butunlike the Y1 receptor, is relatively resistant to the effect of theN-terminal deletion and retains a high binding affinity for theC-terminal fragments such as NPY₁₃₋₃₆ (Blomqvist, A. G. et al. TrendsNeurosci. 1997, 20, 294-298).

NPY itself is the archetypal substrate for the NPY receptors and itsbinding can elicit a variety of pharmacological and biological effectsin vitro and in vivo. When administered to the brain of live animals(intracerebroventricularly (icv) or into the amygdala), NPY producesanxiolytic effects in established animal models of anxiety such as theelevated plus-maze, Vogel punished drinking, and Geller-Seifter'sbar-pressing conflict paradigms (Heilig, M. et al. Psychopharmacology1989, 98, 524; Heilig, M. et al. Regul. Pept. 1992, 41, 61; Heilig, M.et al. Neuropsychopharmacology 1993, 8, 357). Thus, compounds that mimicNPY are postulated to be useful for the treatment of anxiolyticdisorders.

The immunoreactivity of NPY is notably decreased in the cerebrospinalfluid of patients with major depression and those of suicide victims(Widdowson, P. S. et al. J. Neurochem. 1992, 59, 73), and rats treatedwith tricyclic antidepressants display significant increases of NPYrelative to a control group (Heilig, M. et al. Eur. J. Pharmacol. 1988,147, 465). These findings suggest that an inadequate NPY response mayplay a role in some depressive illnesses, and that compounds thatregulate the NPY-ergic system may be useful for the treatment ofdepression.

NPY improves memory and performance scores in animal models of learning(Flood, J. F. et al. Brain Res. 1987, 421, 280) and therefore may serveas a cognition enhancer for the treatment of neurodegenerative diseasessuch as Alzheimer's Disease (AD) as well as AIDS-related and seniledementia.

Elevated plasma levels of NPY are present in animals and humansexperiencing episodes of high sympathetic nerve activity such assurgery, newborn delivery and hemorrhage (Morris, M. J. et. al. J.Auton. Nerv. Syst. 1986, 17, 143). Thus, chemical substances that alterthe NPY-ergic system may be useful for alleviating migraine, pain, andthe condition of stress.

NPY also mediates endocrine functions such as the release of luteinizinghormone (LH) in rodents (Kalra, S. P. et. al. Front. Neuroendrocrinol.1992, 13, 1). Since LH is vital for mammalian ovulation, a compound thatmimics the action of NPY could be useful for the treatment ofinfertility, particularly in women with so-called luteal phase defects.

NPY is a powerful stimulant of food intake; as little as one-billionthof a gram, when injected directly into the CNS, causes satiated rats toovereat (Clark, J. T. et al. Endocrinology 1984, 115, 427; Levine, A. S.et al. Peptides 1984, 5, 1025; Stanley, B. G. et al. Life Sci. 1984, 35,2635; Stanley, B. G. et al. Proc. Nat. Acad. Sci. U.S.A. 1985, 82,3940). Thus NPY is orexigenic in rodents but not anxiogenic when givenintracerebroventricularly and so antagonism of neuropeptide receptorsmay be useful for the treatment of diabetes and eating disorders such asobesity, anorexia nervosa, and bulimia nervosa.

It is known that the anxiolytic properties of NPY are mediated throughpostsynaptic Y1 receptors, whereas presynaptic Y2 receptors negativelycontrol the release of NPY and other cotransmitters (e.g. GABA).Consequently, antagonism of the Y2 receptor may lead to enhancedGABAergic and NPYergic effects and Y2 receptor antagonists should proveuseful in the treatment of depression and anxiety.

Recently, a key role of presynaptic hypothalamic Y2 receptor has beensuggested in central coordination of energy homeostasis and bone massregulation (Herzog, H. et al. Drug News & Perspectives 2002, 15,506-510). Studies analyzing Y2 receptor knockout mice have started tounravel some of the individual functions of this receptor subtype. Y2receptor knockout mice do show a reduced body weight despite an increasein food intake, which is possibly due to the lack of the feedbackinhibition of the postprandially released PYY₃₋₃₆ (Batterham, R. L. etal. Nature 2002, 418, 650-654). The Y2 receptor knockout mice also showa significant increase in bone formation (Baldock, P. A. J. Clin.Invest. 2002, 109, 915-921). Specific deletion of the Y2 receptor in thehypothalamus in adult conditional Y2 receptor knockout mice also causesan increase in bone formation.

Grouzmann and coworkers described a peptide-based ligand, T4-[NPY33-36], which showed considerable affinity (IC₅₀=67 nM) for the NPY Y2receptor (Grouzmann, E., et al. J. Biol. Chem. 1997, 272, 7699-7706).BIIE0246 also binds to the NYP Y2 receptor with significant affinity(IC₅₀=3.3 nM) (Doods, H., et al. Eur. J. Pharmacol. 1999, 384, R3-R5).However, the therapeutic potential for these compounds is limited due totheir peptide-like composition and elevated molecular weight.

Studies also indicate that NPY Y2 is involved in the neurobiologicalresponses to ethanol and other drugs of abuse. Thiele and coworkers(Neuropeptides, 2004, 38(4), 235-243; Peptides 2004, 25(6), 975-983)described the low ethanol consumption of Y2 receptor knockout mice, aswell as their increased voluntary water consumption. Therefore,modulators of NPY Y2 may allow for the treatment of alcohol and drugabuse.

Accordingly, it is an object of the present invention to provide novelnon-peptidic NPY Y2 receptor inhibitors that are useful in modulating ortreating: anxiolytic disorders and depression; a condition requiringtreatment of injured mammalian nerve tissue; a condition amenable totreatment through administration of a neurotrophic factor; aneurological disorder; bone loss; substance related disorders; obesity;an obesity-related disorder; and a condition related to an endocrinefunction including inovulation and infertility.

SUMMARY OF THE INVENTION

The invention provides novel non-peptidic NPY Y2 receptor inhibitors ofthe formula (I):

wherein

-   the fused pyrrolidine ring optionally contains a single    carbon-carbon double bond or a single carbon ring member adjacent to    the nitrogen is optionally ═O substituted;-   n is 1 or 2;-   m is 0, 1, or 2;-   Y₁ is a C₀₋₅ alkylene, C₀₋₅ alkenylene, C₀₋₅ alkynylene,    C₀₋₅acylene; —CH(CONR^(f)R^(g))— (where R^(f) and R^(g) are    independently H or C₁₋₄alkyl), or —CH(CO₂C₁₋₄alkyl)-;-   Y₂ is H, phenyl, C₄₋₈ cycloalkyl or C₄₋₈ cycloalkenyl, each ring    optionally substituted with R^(q);-   Y₃ is —CH₂—, carbonyl or sulfone;-   Y₄ is a substituted or unsubstituted C₂₋₇ alkyl, C₂₋₇ alkenyl, C₂₋₇    alkynyl or C₃₋₇cycloalkyl;-   Y₅ is phenyl, furanyl, thiophenyl, pyrrolyl, pyrrolinyl,    pyrrolidinyl, dioxolanyl, oxazolyl, thiazolyl, imidazolyl,    imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, oxadiazolyl,    triazolyl, thiadiazolyl, pyranyl, pyridyl, piperidinyl, dioxanyl,    morpholinyl, dithianyl, thiomorpholinyl, pyridazinyl, pyrimidinyl,    pyrazinyl, piperazinyl, naphthalenyl, quinolonyl, purinyl, indolyl,    benzofuranyl, or benzothiophenyl, each optionally mono-, di- or    tri-substituted with R^(q);-   R₁ is H or is

-   where R_(a) is H, a substituted or unsubstituted C₁₋₅ alkyl, C₁₋₅    alkenyl, C₁₋₅ alkynyl or C₁₋₅ acyl, where the substituent is    C₁₋₄alkoxy or one or more fluoro;-   R₂ and R₃ are independently selected from H, a substituted or    unsubstituted C₁₋₅ alkyl, C₁₋₅ alkenyl, or C₁₋₅ alkynyl, or R₂ and    R₃ may be taken together with the nitrogen of R₃ attachment to form    piperidine or pyrrolidine or azepine; and-   R^(q) is selected from the group consisting of —OH, —C₁₋₆ alkyl,    —OC₁₋₁₆ alkyl, Ph-, —OPh, benzyl, —Obenzyl, —C₃₋₆ cycloalkyl, —OC₃₋₆    cycloalkyl, —CN, —NO₂, —N(R^(y))R^(z) (wherein R^(y) and R^(z) are    independently selected from H, C₁₋₆ alkyl, C₁₋₆ alkenyl, or R^(y)    and R^(z) may be taken together with the nitrogen of attachment to    form an otherwise aliphatic hydrocarbon ring, said ring having 4 to    7 members, optionally having one carbon replaced with O, ═N—, NH or    N(C₁₋₄alkyl), optionally having one carbon substituted with —OH, and    optionally having one or two unsaturated bonds in the ring),    —(C═O)N(R^(y))R^(z), —(N—R^(t))COR^(t), —(N—R^(t))SO₂C₁₋₆alkyl    (wherein R^(t) is H or C₁₋₆alkyl or two R^(t) in the same    substituent may be taken together with the amide of attachment to    form an otherwise aliphatic hydrocarbon ring, said ring having 4 to    6 members), —(C═O)C₁₋₆alkyl, —(S═(O)_(n))—C₁₋₆alkyl (wherein n is    selected from 0, 1 or 2), —SO₂N(R^(y))R^(z), —SCF₃, halo, —CF₃,    —OCF₃, —COOH and —COOC₁₋₆ alkyl;    and enantiomers, diastereomers, hydrates, solvates and    pharmaceutically acceptable salts, esters and amides thereof.

The invention also features pharmaceutical compositions containing suchcompounds and methods of using such compositions in the treatment orprevention of disease states mediated by NPY Y2 receptor activity.

These and additional aspects of the invention are disclosed in thefollowing detailed description.

DETAILED DESCRIPTION OF THE INVENTION

In a preferred embodiment, the invention provides compounds of formula(I) that have the formula (II):

where R_(b) is H, COCH₃, CHO, COCH₂COCH₃, COCO₂C₂H₅, CH₃, SO₂CH₃, orCOCF₃ and X is 4-CF₃, 3-CF₃, 2-CF₃, 3-Br, 3-F, 3-Cl, 3-CH₃, 3-NO₂, 3-CN,3-SOCF₃, 3,5-diF, 3,5-diCH₃, 3,5-diCl, or 4-Cl.

In another preferred embodiment, the invention provides compounds offormula (I) that have the formula (III):

where R_(c) is N-(1-acetyl)-tetrahydroquinolin-7-yl,2-oxo-2,3-dihydro-1H-indol-6-yl, or N-(1-acetyl)-1H-indol-6-yl and X is4-CF₃, 3-CF₃, 2-CF₃, 3-Br, 3-F, 3-Cl, 3-CH₃, 3-NO₂, 3-CN, 3-SOCF₃,3,5-diF, 3,5-diCH₃, 3,5-diCl, or 4-Cl.

In another preferred embodiment, the invention provides compounds offormula (I) that have the formula (IV):

where R_(d) is COCH₂CH₂C₆H₄X, CO(C₃H₄)C₆H₄X, E-CH₂CH═CHC₆H₄X,E-SO₂CH═CHC₆H₄X, COC≡CC₆H₄X, Z-COCH═CHC₆H₄X, (E,E)-CO(CH═CH)₂C₆H₅,CH═CH₂, E-COCH═CH(3-thiophenyl)X, E-COCH═CH(pyridyl)X,E-COCH═CH(1-hydroxy-pyridyl), or E-COCH═CH(2-imidazolyl)X and X is4-CF₃, 3-CF₃, 2-CF₃, 3-Br, 3-F, 3-Cl, 3-CH₃, 3-NO₂, 3-CN, 3-SOCF₃,3,5-diF, 3,5-diCH₃, 3,5-diCl, or 4-Cl.

In another preferred embodiment, the invention provides compounds offormula (I) that have the formula (V):

where R_(e) is COC₆H₅, CH₂CH₂C₆H₅, CH₂CH₂CH₂C₆H₅, CH(CO₂CH₃)C₆H₅,CH(CONHCH₂CH₃)C₆H₅, CH₂C₆H₁₁, CH₂CH₂C₆H₁₁, or CH₂CH₂C₅H₉, and X is4-CF₃, 3-CF₃, 2-CF₃, 3-Br, 3-F, 3-Cl, 3-CH₃, 3-NO₂, 3-CN, 3-SOCF₃,3,5-diF, 3,5-diCH₃, 3,5-diCl, or 4-Cl.

In another preferred embodiment, the invention provides compounds offormula (I) that have the formula (VI):

where R₂ is H, C₁₋₃alkyl, or allyl and R₃ is H, or R₂ and R₃ are takentogether to be a divalent moiety —CH₂—, m is 1 or 2, and X is 4-CF₃,3-CF₃, 2-CF₃, 3-Br, 3-F, 3-Cl, 3-CH₃, 3-NO₂, 3-CN, 3-SOCF₃, 3,5-diF,3,5-diCH₃, 3,5-diCl, or 4-Cl.

Preferred compounds of the present invention are selected from the groupconsisting of:

EX CHEMICAL NAME 1trans-N-(1-Acetyl-2,3-dihydro-1H-indol-6-yl)-N-(1-benzyl-piperidin-4-yl)-3-phenyl-acrylamide; 2trans-N-(1-Benzyl-piperidin-4-yl)-N-(2,3-dihydro-1H-indol-6-yl)-3-phenyl-acrylamide; 3trans-N-(1-Benzyl-piperidin-4-yl)-N-(1-formyl-2,3-dihydro-1H-indol-6-yl)-3-phenyl-acrylamide; 4trans-N-(1-Benzyl-piperidin-4-yl)-N-[1-(3-oxo-butyryl)-2,3-dihydro-1H-indol-6-yl]-3-phenyl-acrylamide; 5trans-{6-[(1-Benzyl-piperidin-4-yl)-(3-phenyl-acryloyl)-amino]-2,3-dihydro-indol-1-yl}-oxo-acetic acid ethyl ester; 6trans-N-(1-Benzyl-piperidin-4-yl)-N-(1-methyl-2,3-dihydro-1H-indol-6-yl)-3-phenyl-acrylamide; 7trans-N-(1-Benzyl-piperidin-4-yl)-N-(1-methanesulfonyl-2,3-dihydro-1H-indol-6-yl)-3-phenyl-acrylamide; 8trans-N-(1-Benzyl-piperidin-4-yl)-3-phenyl-N-[1-(2,2,2-trifluoro-acetyl)-2,3-dihydro-1H-indol-6-yl]-acrylamide; 9trans-N-(1-Acetyl-1,2,3,4-tetrahydro-quinolin-7-yl)-N-(1-benzyl-piperidin-4-yl)-3-phenyl-acrylamide; 10trans-N-(1-Benzyl-piperidin-4-yl)-N-(2-oxo-2,3-dihydro-1H-indol-6-yl)-3-phenyl-acrylamide; 11trans-N-(1-Acetyl-1H-indol-6-yl)-N-(1-benzyl-piperidin-4-yl)-3-phenyl-acrylamide; 12N-(1-Acetyl-2,3-dihydro-1H-indol-6-yl)-N-(1-benzyl-piperidin-4-yl)-3-phenyl-propionamide; 13 trans-2-Phenyl-cyclopropanecarboxylic acid(1-acetyl-2,3- dihydro-1H-indol-6-yl)-(1-benzyl-piperidin-4-yl)-amide;14 trans-1-{6-[(1-Benzyl-piperidin-4-yl)-(3-phenyl-allyl)-amino]-2,3-dihydro-indol-1-yl}-ethanone; 15 trans-2-Phenyl-ethenesulfonic acid(1-acetyl-2,3-dihydro-1H- indol-6-yl)-(1-benzyl-piperidin-4-yl)-amide;16 3-Phenyl-propynoic acid (1-acetyl-2,3-dihydro-1H-indol-6-yl)-(1-benzyl-piperidin-4-yl)-amide; 17cis-N-(1-Acetyl-2,3-dihydro-1H-indol-6-yl)-N-(1-benzyl-piperidin-4-yl)-3-phenyl-acrylamide; 18 trans,trans-5-Phenyl-penta-2,4-dienoicacid (1-acetyl-2,3-dihydro-1H-indol-6-yl)-(1-benzyl-piperidin-4-yl)-amide; 19N-(1-Acetyl-2,3-dihydro-1H-indol-6-yl)-N-(1-benzyl-piperidin-4-yl)-acrylamide; 20trans-N-(1-Acetyl-2,3-dihydro-1H-indol-6-yl)-N-(1-benzyl-piperidin-4-yl)-3-thiophen-3-yl-acrylamide; 21trans-N-(1-Acetyl-2,3-dihydro-1H-indol-6-yl)-N-(1-benzyl-piperidin-4-yl)-3-pyridin-2-yl-acrylamide; 22trans-N-(1-Acetyl-2,3-dihydro-1H-indol-6-yl)-N-(1-benzyl-piperidin-4-yl)-3-pyridin-3-yl-acrylamide; 23trans-N-(1-Acetyl-2,3-dihydro-1H-indol-6-yl)-N-(1-benzyl-piperidin-4-yl)-3-pyridin-4-yl-acrylamide; 24trans-N-(1-Acetyl-2,3-dihydro-1H-indol-6-yl)-N-(1-benzyl-piperidin-4-yl)-3-(1-oxy-pyridin-4-yl)-acrylamide; 25trans-N-(1-Acetyl-2,3-dihydro-1H-indol-6-yl)-N-(1-benzyl-piperidin-4-yl)-3-(1H-imidazol-2-yl)-acrylamide; 26trans-N-(1-Acetyl-2,3-dihydro-1H-indol-6-yl)-N-(1-benzyl-piperidin-4-yl)-3-(4-trifluoromethyl-phenyl)-acrylamide; 27trans-N-(1-Acetyl-2,3-dihydro-1H-indol-6-yl)-N-(1-benzyl-piperidin-4-yl)-3-(3-trifluoromethyl-phenyl)-acrylamide; 28trans-N-(1-Acetyl-2,3-dihydro-1H-indol-6-yl)-N-(1-benzyl-piperidin-4-yl)-3-(2-trifluoromethyl-phenyl)-acrylamide; 29trans-N-(1-Acetyl-2,3-dihydro-1H-indol-6-yl)-N-(1-benzyl-piperidin-4-yl)-3-(3-bromo-phenyl)-acrylamide; 30trans-N-(1-Acetyl-2,3-dihydro-1H-indol-6-yl)-N-(1-benzyl-piperidin-4-yl)-3-(3-fluoro-phenyl)-acrylamide; 31trans-N-(1-Acetyl-2,3-dihydro-1H-indol-6-yl)-N-(1-benzyl-piperidin-4-yl)-3-(3-chloro-phenyl)-acrylamide; 32trans-N-(1-Acetyl-2,3-dihydro-1H-indol-6-yl)-N-(1-benzyl-piperidin-4-yl)-3-m-tolyl-acrylamide; 33trans-N-(1-Acetyl-2,3-dihydro-1H-indol-6-yl)-N-(1-benzyl-piperidin-4-yl)-3-(3-nitro-phenyl)-acrylamide; 34trans-N-(1-Acetyl-2,3-dihydro-1H-indol-6-yl)-N-(1-benzyl-piperidin-4-yl)-3-(3-cyano-phenyl)-acrylamide; 35trans-N-(1-Acetyl-2,3-dihydro-1H-indol-6-yl)-N-(1-benzyl-piperidin-4-yl)-3-(3-trifluoromethanesulfinyl-phenyl)-acrylamide; 36trans-N-(1-Acetyl-2,3-dihydro-1H-indol-6-yl)-N-(1-benzyl-piperidin-4-yl)-3-(3,5-difluoro-phenyl)-acrylamide; 37trans-N-(1-Acetyl-2,3-dihydro-1H-indol-6-yl)-N-(1-benzyl-piperidin-4-yl)-3-(3,5-dimethyl-phenyl)-acrylamide; 38trans-N-(1-Acetyl-2,3-dihydro-1H-indol-6-yl)-N-(1-benzyl-piperidin-4-yl)-3-(3,5-dichloro-phenyl)-acrylamide; 39trans-N-(1-Acetyl-2,3-dihydro-1H-indol-6-yl)-N-(1-benzoyl-piperidin-4-yl)-3-phenyl-acrylamide; 40trans-N-(1-Acetyl-2,3-dihydro-1H-indol-6-yl)-N-(1-phenethyl-piperidin-4-yl)-3-phenyl-acrylamide; 41trans-N-(1-Acetyl-2,3-dihydro-1H-indol-6-yl)-3-phenyl-N-[1-(3-phenyl-propyl)-piperidin-4-yl]-acrylamide; 42trans-N-(1-Acetyl-2,3-dihydro-1H-indol-6-yl)-N-(1-cyclohexylmethyl-piperidin-4-yl)-3-phenyl-acrylamide; 43trans-N-(1-Acetyl-2,3-dihydro-1H-indol-6-yl)-N-[1-(2-cyclohexyl-ethyl)-piperidin-4-yl]-3-phenyl-acrylamide; 44trans-N-(1-Acetyl-2,3-dihydro-1H-indol-6-yl)-N-[1-(2-cyclopentyl-ethyl)-piperidin-4-yl]-3-phenyl-acrylamide; 45trans-N-(1-Acetyl-2,3-dihydro-1H-indol-6-yl)-N-(1-benzyl-piperidin-3-yl)-3-phenyl-acrylamide; 46trans-N-(1-Acetyl-2,3-dihydro-1H-indol-6-yl)-N-(1-benzyl-pyrrolidin-3-yl)-3-phenyl-acrylamide; 47trans-N-(1-Acetyl-2,3-dihydro-1H-indol-6-yl)-N-(3-benzylamino-propyl)-3-phenyl-acrylamide; 48trans-N-(1-Acetyl-2,3-dihydro-1H-indol-6-yl)-N-[3-(allyl-benzyl-amino)-propyl]-3-phenyl-acrylamide; 49trans-N-(1-Acetyl-2,3-dihydro-1H-indol-6-yl)-3-(4-chloro-phenyl)-N-[1-(2-cyclohexyl-ethyl)-piperidin-4-yl]-acrylamide; 50trans-N-(1-Acetyl-2,3-dihydro-1H-indol-6-yl)-N-[1-(2-cyclohexyl-ethyl)-piperidin-4-yl]-3-(3-nitro-phenyl)-acrylamide; 51trans-N-(1-Acetyl-2,3-dihydro-1H-indol-6-yl)-3-(4-chloro-phenyl)-N-[1-(2-cyclopentyl-ethyl)-piperidin-4-yl]-acrylamide; 52trans-N-(1-Acetyl-2,3-dihydro-1H-indol-6-yl)-N-[1-(2-cyclopentyl-ethyl)-piperidin-4-yl]-3-(3-nitro-phenyl)-acrylamide; 53trans-N-(1-Acetyl-2,3-dihydro-1H-indol-6-yl)-3-(3-cyano-phenyl)-N-[1-(2-cyclopentyl-ethyl)-piperidin-4-yl]-acrylamide; 54trans-N-(1-Acetyl-2,3-dihydro-1H-indol-6-yl)-N-(1-benzyl-piperidin-4-yl)-3-(4-chloro-phenyl)-acrylamide; 55trans-{4-[(1-Acetyl-2,3-dihydro-1H-indol-6-yl)-(3-phenyl-acryloyl)-amino]-piperidin-1-yl}-phenyl-acetic acid methyl ester; and 56trans-N-(1-Acetyl-2,3-dihydro-1H-indol-6-yl)-N-[1-(ethylcarbamoyl-phenyl-methyl)-piperidin-4-yl]-3-phenyl- acrylamide.

Although all the compounds of formula (I) are novel for the uses and inthe formulations taught herein, not all compounds of formula I are novelas such. The compound of the structure:

was available from Peakdale Molecular (ID# PRD-0817) prior to the dateof the present invention.

The present invention includes the pharmaceutically acceptable acidaddition salts of compounds of formula (I). The acids which are used toprepare the pharmaceutically acceptable acid addition salts of theaforementioned base compounds of this invention are those which formnon-toxic acid addition salts, i.e., salts containing pharmacologicallyacceptable anions, such as the hydrochloride, hydrobromide,hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate,oleate, palmitate, stearate, laurate, borate, benzoate, lactate,phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate,naphthylate, mesylate, glucoheptonate, lactiobionate, saccharate,ethanesulfonate, benzenesulfonate, and pamoate [i.e.,1,1′-methylene-bis-(2-hydroxy-3 naphthoate)] salts.

The invention also includes base addition salts of formula (I). Thechemical bases that may be used as reagents to prepare pharmaceuticallyacceptable base salts of those compounds of formula (I) that are acidicin nature are those that form non-toxic base salts with such compounds.Such non-toxic base salts include, but are not limited to those derivedfrom such pharmacologically acceptable cations such as alkali metalcations (e.g., potassium and sodium) and alkaline earth metal cations(e, calcium and magnesium), ammonium or water-soluble amine additionsalts such as N-methylglucamine (meglumine), and the loweralkanolammonium and other base salts of pharmaceutically acceptableorganic amines. See example, S. M. Berge, et al., “PharmaceuticalSalts,” J. Pharm. Sci., 1977, 66:1-19, which is incorporated herein byreference.

Representative pharmaceutically acceptable amides of the inventioninclude those derived from ammonia, primary C₁₋₆ alkyl amines andsecondary di(C₁₋₆alkyl) amines. Secondary amines include 5- or6-membered heterocyclic or heteroaromatic ring moieties containing atleast one nitrogen atom and optionally between 1 and 2 additionalheteroatoms. Preferred amides are derived from ammonia, C₁₋₃alkylprimary amines, and di(C₁₋₂alkyl)amines. Representative pharmaceuticallyacceptable esters of the invention include C₁₋₇alkyl, C₅₋₇cycloalkyl,phenyl, and phenyl(C₁₋₆)alkyl esters. Preferred esters include methylesters.

The compounds of this invention include all stereoisomers (i.e., cis andtrans isomers) and all optical isomers of compounds of the formula (I)(e.g., R and S enantiomers), as well as racemic, diastereomeric andother mixtures of such isomers, as well as all polymorphs of thecompounds.

The features and advantages of the invention are apparent to one ofordinary skill in the art. Based on this disclosure, including thesummary, detailed description, background, examples, and claims, one ofordinary skill in the art will be able to make modifications andadaptations to various conditions and usages. Publications describedherein are incorporated by reference in their entirety.

Representative compounds of the present invention can be synthesized inaccordance with the general synthetic methods described below. Since thescheme is an illustration, the invention should not be construed asbeing limited by the chemical reactions and conditions expressed. Thepreparation of the various starting materials used in the schemes iswell within the skill of persons versed in the art.

The compounds of formula (I) of the invention may be produced by anynumber of reaction schemes. Referring to Scheme A, wherein Y₁-Y₅, R₁₋₃,and n are as defined previously, a 1-substituted-6-aminoindoline A1 canbe reacted with ketone (A2) under conditions of a reductive amination toform amine (A3). The reaction is typically performed using Na(OAc)₃BH asthe reducing agent in the presence of AcOH, in a solvent such as CH₂Cl₂or 1,2-dichloroethane. The amine (A3) is then reacted with a carboxylicacid under peptide coupling conditions, with a sulfonyl chloride or anacyl chloride in the presence of a suitable base such as triethylamine,or with an alkyl halide, to form derivative (I). Acyl chlorides usefulin the transformation can also be prepared from commercially availablecarboxylic acids using oxalyl chloride and catalytic DMF. Suitableprotecting groups are used where appropriate throughout the synthesis.

Referring to Scheme B, the compounds of formula (I) may be prepared byan alternate method. Amine (A3) is converted to phosphonate (B1) byreaction with an appropriate phosphonoacetic acid ester. Typically amixture of amine (A3) and the phosphonoacetic acid ester is heated atreflux in a hydrocarbon solvent such as xylenes, with or without theaddition of catalytic DMAP. Phosphonate (B1) is then coupled with anappropriate aldehyde to form enamide (I). The cis and trans double bondisomers are independently accessible using this sequence. Suitableconditions for obtaining the trans isomer involve use of the phosphonicacid diethyl ester (B1) in the presence of LiCl and DBU in acetonitrile.The cis isomer can be obtained by reacting the phosphonic acidbis-(2,2,2-trifluoro-ethyl) ester (B1) with a base such as potassiumbis(trimethylsilyl)amide in the presence of a solvating agent such as18-crown-6.

It is generally preferred that the respective product of each processstep be separated from other components of the reaction mixture andsubjected to purification before its use as a starting material in asubsequent step. Separation techniques typically include evaporation,extraction, precipitation and filtration. Purification techniquestypically include column chromatography (Still, W. C., et al., J. Org.Chem. 1978, 43, 2921), thin-layer chromatography, crystallization anddistillation.

As used herein, the following terms have the following respectivemeanings. Other terms that are used to describe the present inventionhave the same definitions as those generally used by those skilled inthe art. Specific examples recited in any definition are not intended tobe limiting in any way.

“Hydrocarbon” refers to a substituted or unsubstituted organic compound.

“Acetal” refers to a compound in which two ether oxygens are bound tothe same carbon. A “ketal” is an acetal derived from a ketone (acompound of the formula RR′CO, where R and R′ are alkyl, aryl, orheterocyclic radicals).

“Acyloxy” refers to the groups alkyl-C(O)O—, substituted alkyl-C(O)O—,cycloalkyl-C(O)O—, substituted cycloalkyl-C(O)O—, aryl-C(O)O—,heteroaryl-C(O)O—, and heterocyclic-C(O)O— wherein alkyl, substitutedalkyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl, andheterocyclic are as defined herein.

“Acyl” means a compound of the formula RCO, where R is aliphatic(characterized by a straight chain of carbon atoms), alicyclic (asaturated hydrocarbon containing at least one ring), or aromatic.

“Alkyl” refers to a fully saturated monovalent hydrocarbon radicalcontaining carbon and hydrogen, which may be a straight chain, branched,or cyclic. Examples of alkyl groups are methyl, ethyl, n-butyl,n-heptyl, isopropyl, 2-methylpropyl, cyclopropyl, cyclopropylmethyl,cyclobutyl, cyclopentyl, cyclopentylethyl and cyclohexyl. “Cycloalkyl”groups refer to cyclic alkyl groups such as cyclopropyl, cyclobutyl,cyclopentyl and cyclohexyl. C₁-C₇ alkyl groups are preferably used inthe present invention.

“Substituted alkyl” refers to alkyls as just described which include oneor more functional groups such an alkyl containing from 1 to 6 carbonatoms, preferably a lower alkyl containing 1-3 carbon atoms, aryl,substituted aryl, acyl, halogen (i.e., alkyl halos, e.g., CF₃), hydroxy,alkoxy, alkoxyalkyl, amino, alkyl and dialkyl amino, acylamino, acyloxy,aryloxy, aryloxyalkyl, carboxyalkyl, carboxamido, thio, thioethers, bothsaturated and unsaturated cyclic hydrocarbons, heterocycles and thelike. The term “substituted cycloalkyl” has essentially the samedefinition as and is subsumed under the term “substituted alkyl” forpurposes of describing the present invention. An “alkyl phenone” is anaromatic ketone bound to an alkyl; an “alkenyl phenone is an aromaticketone bound to an alkylene.

“Amine” refers to substituted or unsubstituted aliphatic amines (e.g.,ethyl amine), aromatic amines (e.g., aniline), saturated heterocyclicamines (e.g., piperidine), substituted derivatives such as an alklymorpoline, aromatic heterocyclic compounds including but not limited topyridine, purine, or indoline.

“Aralkyl” refers to an alkyl group with an aryl substituent, and theterm “aralkylene” refers to an alkenyl group with an aryl substituent;the term “alkaryl” refers to an aryl group that has an alkylsubstituent, and the term “alkarylene” refers to an arylene group withan alkyl substituent.

“Alkenyl” refers to a branched or unbranched hydrocarbon group typicallyalthough not necessarily containing 2 to about 24 carbon atoms and atleast one double bond, such as ethenyl, n-propenyl, isopropenyl,n-butenyl, isobutenyl, octenyl, decenyl, and the like. Generally, thoughnot necessarily, alkenyl groups herein contain 2 to about 12 carbonatoms. The term “lower alkenyl” intends an alkenyl group of two to sixcarbon atoms, preferably two to four carbon atoms.

“Substituted alkenyl” refers to alkenyl substituted with one or moresubstituent groups, and the terms “heteroatom-containing alkenyl” and“heteroalkenyl” refer to alkenyl in which at least one carbon atom isreplaced with a heteroatom.

“Aryl” refers to a substituted or unsubstituted monovalent aromaticradical having a single ring (e.g., phenyl) or multiple condensed rings(e.g., naphthyl). Other examples include heterocyclic aromatic ringgroups having one or more nitrogen, oxygen, or sulfur atoms in the ring,such as imidazolyl, furyl, pyrrolyl, pyridyl, thienyl and indolyl, amongothers. The term “arylene” refers to the diradical derived from aryl(including substituted aryl) as exemplified by 1,2-phenylene,1,3-phenylene, 1,4-phenylene, 1,2-naphthylene and the like.

“Substituted aryl” refers to an aryl as just described that contains oneor more functional groups such as lower alkyl, acyl, aryl, halogen,alkylhalos (e.g., CF₃), hydroxy, alkoxy, alkoxyalkyl, amino, alkyl anddialkyl amino, acylamino, acyloxy, aryloxy, aryloxyalkyl, carboxyalkyl,carboxamido, thio, thioethers, both saturated and unsaturated cyclichydrocarbons, heterocycles and the like.

“Alkynyl” as used herein refers to a branched or unbranched hydrocarbongroup typically although not necessarily containing 2 to about 24 carbonatoms and at least one triple bond, such as ethynyl, n-propynyl,isopropynyl, n-butynyl, isobutynyl, octynyl, decynyl, and the like.Generally, although again not necessarily, alkynyl groups herein contain2 to about 12 carbon atoms. The term “lower alkynyl” intends an alkynylgroup of two to six carbon atoms, preferably three or four carbon atoms.“Substituted alkynyl” refers to alkynyl substituted with one or moresubstituent groups, and the terms “heteroatom-containing alkynyl” and“heteroalkynyl” refer to alkynyl in which at least one carbon atom isreplaced with a heteroatom.

“Alkoxy” as used herein refers to an alkyl group bound through an etherlinkage; that is, an “alkoxy” group may be represented as —O-alkyl wherealkyl is as defined above. A “lower alkoxy” group intends an alkoxygroup containing one to six, more preferably one to four, carbon atoms.

“Allenyl” is used herein in the conventional sense to refer to the group—CH═C═CH₂. An “allenyl” group may be unsubstituted or substituted withone or more non-hydrogen substituents.

“Anomer” as used herein means one of a pair of isomers of a cycliccarbohydrate resulting from creation of a new point of symmetry when arearrangement of atoms occurs at an aldehyde or ketone position.

“Halo” and “halogen” are used in the conventional sense to refer to achloro, bromo, fluoro or iodo substituent. The terms “haloalkyl,”“haloalkenyl” or “haloalkynyl” (or “halogenated alkyl,” “halogenatedalkenyl,” or “halogenated alkynyl”) refer to an alkyl, alkenyl oralkynyl group, respectively, in which at least one of the hydrogen atomsin the group has been replaced with a halogen atom.

“Heterocycle” or “heterocyclic” refers to a carbocylic ring wherein oneor more carbon atoms have been replaced with one or more heteroatomssuch as nitrogen, oxygen or sulfur. Examples of heterocycles include,but are not limited to, furan, thiphene, pyrrole, pyrroline,pyrrolidine, dioxolane, oxazole, thiazole, imidazole, imidazolie,imidazolidine, pyrazole, pyrazoline, pyrazolidine, oxadiazole, triazole,thiadiazole, pyran, pyridine, piperidine, dioxane, morpholine, dithiane,thiomorpholine, pyridazine, pyrimidine, pyrazine, piperazine, triazine,trithiane, naphthalene, quinolone, purine, indole, benzofuran, orbenzothiophene.

“Heteroatom-containing” refers to a molecule or molecular fragment inwhich one or more carbon atoms is replaced with an atom other carbon,e.g., nitrogen, oxygen, sulfur, phosphorus or silicon.

“Substituted heterocycle” refers to a heterocycle as just described thatcontains one or more functional groups such as lower alkyl, acyl, aryl,cyano, halogen, hydroxy, alkoxy, alkoxyalkyl, amino, alkyl and dialkylamino, acylamino, acyloxy, aryloxy, aryloxyalkyl, carboxyalkyl,carboxamido, thio, thioethers, both saturated and unsaturated cyclichydrocarbons, heterocycles and the like. In other instances where theterm “substituted” is used, the substituents which fall under thisdefinition may be readily gleaned from the other definitions ofsubstituents which are presented in the specification as well thecircumstances under which such substituents occur in a given chemicalcompound.

“Substituted” as in “substituted alkyl” or “substituted alkenyl” meansthat in the hydrocarbyl, hydrocarbylene, alkyl, alkenyl or other moiety,at least one hydrogen atom bound to a carbon atom is replaced with oneor more substituents that are functional groups such as hydroxyl,alkoxy, thio, amino, halo, silyl, and the like. When the term“substituted” appears prior to a list of possible substituted groups, itis intended that the term apply to every member of that group.

“Effective amount” refers to the amount of a selected compound,intermediate, or reactant that is used to produce an intended result.The precise amount of a compound, intermediate, or reactant used willvary depending upon the particular compound selected and its intendeduse, the age and weight of the subject, route of administration, and soforth, but may be easily determined by routine experimentation. In thecase of the treatment of a condition or disease state, an effectiveamount is that amount which is used to effectively treat the particularcondition or disease state.

The term “subjects” is used throughout the specification to describe ananimal, preferably a human, to whom treatment, including prophylactictreatment, with the compositions according to the present invention isprovided.

The compositions of the present invention may be formulated in aconventional manner using one or more pharmaceutically acceptablecarriers. Pharmaceutically acceptable carriers that may be used in thesepharmaceutical compositions include, but are not limited to, ionexchangers, alumina, aluminum stearate, lecithin, serum proteins, suchas human serum albumin, buffer substances such as phosphates, glycine,sorbic acid, potassium sorbate, partial glyceride mixtures of saturatedvegetable fatty acids, water, salts or electrolytes, such as prolaminesulfate, disodium hydrogen phosphate, potassium hydrogen phosphate,sodium chloride, zinc salts, colloidal silica, magnesium trisilicate,polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol,sodium carboxymethylcellulose, polyacrylates, waxes,polyethylene-polyoxypropylene-block polymers, polyethylene glycol andwool fat.

The compositions of the present invention may be administered orally,parenterally, by inhalation spray, topically, rectally, nasally,buccally, vaginally or via an implanted reservoir. The term “parenteral”as used herein includes subcutaneous, intravenous, intramuscular,intra-articular, intra-synovial, intrasternal, intrathecal,intrahepatic, intralesional and intracranial injection or infusiontechniques. Preferably, the compositions are administered orally,intraperitoneally, or intravenously.

Sterile injectable forms of the compositions of this invention may beaqueous or oleaginous suspension. These suspensions may be formulatedaccording to techniques known in the art using suitable dispersing orwetting agents and suspending agents. The sterile injectable preparationmay also be a sterile injectable solution or suspension in a non-toxicparenterally-acceptable diluent or solvent, for example as a solution in1,3-butanediol. Among the acceptable vehicles and solvents that may beemployed are water, Ringer's solution and isotonic sodium chloridesolution. In addition, sterile, fixed oils are conventionally employedas a solvent or suspending medium. For this purpose, any bland fixed oilmay be employed including synthetic mono- or di-glycerides. Fatty acids,such as oleic acid and its glyceride derivatives are useful in thepreparation of injectables, as are natural pharmaceutically-acceptableoils, such as olive oil or castor oil, especially in theirpolyoxyethylated versions. These oil solutions or suspensions may alsocontain a long-chain alcohol diluent or dispersant, such as Ph. Helv orsimilar alcohol.

The pharmaceutical compositions of this invention may be orallyadministered in any orally acceptable dosage form including, but notlimited to, capsules, tablets, aqueous suspensions or solutions. In thecase of tablets for oral use, carriers that are commonly used includelactose and corn starch. Lubricating agents, such as magnesium stearate,are also typically added. For oral administration in a capsule form,useful diluents include lactose and dried cornstarch. When aqueoussuspensions are required for oral use, the active ingredient is combinedwith emulsifying and suspending agents. If desired, certain sweetening,flavoring or coloring agents may also be added.

Alternatively, the pharmaceutical compositions of this invention may beadministered in the form of suppositories for rectal administration.These can be prepared by mixing the agent with a suitable non-irritatingexcipient that is solid at room temperature but liquid at rectaltemperature and therefore will melt in the rectum to release the drug.Such materials include cocoa butter, beeswax and polyethylene glycols.

The pharmaceutical compositions of this invention may also beadministered topically, especially when the target of treatment includesareas or organs readily accessible by topical application, includingdiseases of the eye, the skin, or the lower intestinal tract. Suitabletopical formulations are readily prepared for each of these areas ororgans.

Topical application for the lower intestinal tract can be effected in arectal suppository formulation (see above) or in a suitable enemaformulation. Topically-transdermal patches may also be used.

For topical applications, the pharmaceutical compositions may beformulated in a suitable ointment containing the active componentsuspended or dissolved in one or more carriers. Carriers for topicaladministration of the compounds of this invention include, but are notlimited to, mineral oil, liquid petrolatum, white petrolatum, propyleneglycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax andwater. Alternatively, the pharmaceutical compositions can be formulatedin a suitable lotion or cream containing the active components suspendedor dissolved in one or more pharmaceutically acceptable carriers.Suitable carriers include, but are not limited to, mineral oil, sorbitanmonostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol,2-octyldodecanol, benzyl alcohol and water.

For ophthalmic use, the pharmaceutical compositions may be formulated asmicronized suspensions in isotonic, pH adjusted sterile saline, or,preferably, as solutions in isotonic, pH adjusted sterile saline, eitherwith or without a preservative such as benzylalkonium chloride.Alternatively, for ophthalmic uses, the pharmaceutical compositions maybe formulated in an ointment such as petrolatum.

The pharmaceutical compositions of this invention may also beadministered by nasal aerosol or inhalation. Such compositions areprepared according to techniques well-known in the art of pharmaceuticalformulation and may be prepared as solutions in saline, employing benzylalcohol or other suitable preservatives, absorption promoters to enhancebioavailability, fluorocarbons, and/or other conventional solubilizingor dispersing agents.

The amount of a novel NPYY2 inhibitor of the instant invention that maybe combined with the carrier materials to produce a single dosage formwill vary depending upon the host treated, and the particular mode ofadministration. Preferably, the compositions should be formulated tocontain between about 10 milligrams to about 500 milligrams of activeingredient.

It should also be understood that a specific dosage and treatmentregimen for any particular patient will depend upon a variety offactors, including the activity of the specific compound employed, theage, body weight, general health, sex, diet, time of administration,rate of excretion, drug combination, and the judgment of the treatingphysician and the severity of the particular disease or condition beingtreated.

Compounds of the invention are potent, non-peptidic, low molecularweight, selective NPY Y2 inhibitors and are useful in the treating orpreventing: anxiolytic disorders and depression; injured mammalian nervetissue; conditions responsive to treatment through administration of aneurotrophic factor; neurological disorders; bone loss; substancerelated disorders; and metabolic disorders such as obesity or anobesity-related disorder. Compounds of the invention modulate endocrinefunctions; particularly those controlled by the pituitary andhypothalamic glands, and therefore may be used to treat inovulation andinfertility that may be due to insufficient release of luteinizinghormone (LH) or luteal phase defect.

The compounds compete with the endogenous ligands NPY and possiblynon-endogenous ligands, and bind to the NPY2 receptor. In addition, thecompounds demonstrate antagonist activity by antagonizing the action ofNPY upon binding to the Y2 receptor. The compounds described herein areligands of the NPY2 receptor, but are not necessarily limited solely intheir pharmacological or biological action due to binding to this or anyneuropeptide, neurotransmitter or G-protein coupled receptor. Forexample, the described compounds may also undergo binding to dopamine orserotonin receptors.

“Anxiolytic disorders” include affective disorders such as all types ofdepression, bipolar disorder, cyclothymia, and dysthymia, anxietydisorders such as generalized anxiety disorder, panic, phobias andobsessive-compulsive disorder, stress disorders including post-traumaticstress disorder, hemorrhagic stress, stress-induced psychotic episodes,psychosocial dwarfism, stress headaches, stress-induced immune systemsdisorders such as stress-induced fever, and stress-related sleepdisorders, and can include eating disorders such as anorexia nervosa,bulimia nervosa, and obesity, and drug addiction.

“Depression” refers to major depressive disorders, dysthymia, bipolar ormanic disorders, and the like.

“Nerve tissue” as used herein refers to any vertebrate nerve tissue,particularly including mammalian cells of the central nervous system(CNS) and peripheral nervous system (PNS). More particularly, nervetissue includes spinal cord neuronal structures, peripheral nervoussystem nerves, and even nerve cells of the brain.

“Nerve tissue injury”, “injured mammalian nerve tissue”, or “CNS or PNSnerve tissue injury” include any damage to relevant nerve tissueirrespective of cause, e.g., injuries attributable to trauma includingbut not limited to nerve tissue lesions, traumatically-inducedcompression, tumors, hemorrhage, infectious processes, spinal stenosis,or impaired blood supply.

“Treating injured mammalian nerve tissue” includes, but is not limited,to the in vivo administration of compounds, compositions, and methods ofthe instant invention to restore action potential or nerve impulseconduction through a nerve tissue lesion. The term may also include suchadministration in an effort to reduce the damaging effects of any injuryto mammalian nerve tissue, whether through restoration of actionpotential or nerve impulse conduction, by stimulating growth orproliferation of nervous tissue, by ameliorating unwanted conditions inthe extracellular microenvironment near an injury, or otherwise.

“Neurotrophic factor”, as used herein, refers to compounds that arecapable of stimulating growth or proliferation of nervous tissue,including compounds of the instant invention and known neurotrophicfactors described previously herein.

“Neurological disorders” include CNS disorders such as tinitus,spasticity, and neuropathic pain, supranuclear palsy, AIDS relateddementias, multiinfarct dementia, neurodegenerative disorders such asAlzheimer's disease, Parkinson's disease, and Huntington's disease, headtrauma, spinal cord trauma, ischemic neuronal damage, amyotrophiclateral sclerosis, and disorders of pain perception such as fibromyalgiaand epilepsy.

“Bone loss” refers to enhancement of bone growth or prevention of boneloss caused by conditions such as osteoporosis, osteomalacia, Paget'sdisease, disorders of bone homeostasis, and the like.

“Substance related disorders” refer to misuse, addiction, or dependencedisorders related to the consumption of alcohol, amphetamines, cannabis,hallucinogens, inhalants, nicotine, opioids, phencyclidine, orsedatives.

“Obesity” refers to a condition in which a subject has a body mass indexof greater than or equal to 30. “Over-weight” refers to a condition inwhich a subject has a body mass index of greater or equal to 25.0. Thebody mass index and other definitions are according to the “NIH ClinicalGuidelines on the Identification and Evaluation, and Treatment ofOverweight and Obesity in Adults” (1998).

“Obesity-related disorder” includes anorexia nervosa, wasting,AIDS-related weight loss, bulimia, cachexia, lipid disorders includinghyperlipidemia and hyperuricemia, insulin resistance, noninsulindependent diabetes mellitus (NIDDM, or Type II diabetes), insulindependent diabetes mellitus (IDDM or Type I diabetes), diabetes-relatedcomplications including microangiopathic lesions, ocular lesions,retinopathy, neuropathy, and renal lesions, cardiovascular diseaseincluding cardiac insufficiency, coronary insufficiency, and high bloodpressure, atherosclerosis, atheromatous disease, stroke, hypertension,Syndrome X, gallbladder disease, osteoarthritis, sleep apnea, forms ofcancer such as uterine, breast, colorectal, kidney, and gallbladder,high cholesterol levels, complications of pregnancy, menstrualirregularities, hirsutism, muscular dystrophy, infertility, andincreased surgical risk.

EXAMPLES

In order to illustrate the invention, the following examples areincluded. These examples do not limit the invention. They are only meantto suggest a method of practicing the invention. Those skilled in theart may find other methods of practicing the invention, which areobvious to them. However, those methods are deemed to be within thescope of this invention. Unless otherwise noted, the materials used inthe examples were obtained from readily available commercial sources orsynthesized by standard methods known to those skilled in the art.

Protocol for Preparative Reversed-Phase HPLC Gilson® LiquidChromatograph Column: YMC-Pack ODS-A, 5 μm, 75×30 mm

Flow rate: 10 mL/min

Detection: λ=220 & 254 nm

Mobile Phase: (10 to 95% acetonitrile/water, 0.05% trifluoroacetic acid)

Protocol for LC/MS (Reversed-Phase) Hewlett Packard Series 1100 Column:Agilent ZORBAX® C8, 5 μm, 4.6×150 mm

Flow rate: 1 mL/min

Detection: λ=220 & 254 nm Ionization Method: ESI

Gradient: acetonitrile/water, 0.05% trifluoroacetic acid

Mass spectra were obtained on an Agilent series 1100 MSD usingelectrospray ionization (ESI) in either positive or negative modes asindicated. Preparative thin-layer chromatography was performed usingMerck silica gel 60 F₂₅₄ plates measuring 20 cm×20 cm×0.5 mm.

NMR spectra were obtained on either a Bruker model DPX400 (400 MHz) orDPX500 (500 MHz) spectrometer. The format of the ¹H NMR data below is:chemical shift in ppm down field of the tetramethylsilane reference(multiplicity, coupling constant J in Hz, integration).

Example 1

trans-N-(1-Acetyl-2,3-dihydro-1H-indol-6-yl)-N-(1-benzyl-piperidin-4-yl)-3-phenyl-acrylamide

To a solution of1-[6-(1-benzyl-piperidin-4-ylamino)-2,3-dihydro-indol-1-yl]-ethanone(250 mg, 0.72 mmol) in CH₂Cl₂ (10 mL) was added cinnamoyl chloride (160mg, 0.93 mmol) and triethylamine (TEA, 0.30 mL, 2.2 mmol). The mixturewas stirred at 25° C. for 16 h. After concentration, the residue waspurified by preparative TLC (PTLC, 20% EtOAc/CH₂Cl₂) to provide 290 mg(85%) of the desired product. ¹H NMR (500 MHz, CDCl₃): 8.05 (s, 1H),7.62 (d, J=15.5 Hz, 1H), 7.32-7.20 (m, 10H), 7.17 (d, J=7.9 Hz, 1H),6.74 (dd, J=6.8, 1.5 Hz, 1H), 6.15 (d, J=15.5 Hz, 1H), 4.80-4.69 (m,1H), 4.20-4.09 (m, 3H), 3.51-3.45 (m, 1H), 3.31-3.20 (m, 2H), 2.95-2.82(m, 2H), 2.23 (s, 3H), 2.19-2.08 (m, 2H), 1.91-1.71 (m, 2H). MS: exactmass calculated for C₃₁H₃₃N₃O₂, 479.26; m/z found, 480.3 [M+H]⁺.

Example 2

trans-N-(1-Benzyl-piperidin-4-yl)-N-(2,3-dihydro-1H-indol-6-yl)-3-phenyl-acrylamideStep A. 6-Amino-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester

To a mixture of 6-nitroindoline (2 mmol) and TEA (2.2 mmol) in CH₂Cl₂(20 mL) was added di-tert-butyl dicarbonate (2 mmol). The mixture wasstirred at 25° C. for 16 h. The mixture was washed with satd. aq. NaHCO₃(20 mL) and brine (20 mL), and then was dried and concentrated. Theresidue was dissolved in MeOH (4 mL), and FeCl₃.6H₂O (7 mg), Me₂NNH₂ (21mmol), and charcoal (50 mg) were added. The resulting mixture was heatedat reflux for 4 h. The mixture was filtered through diatomaceous earthand the filtrate was concentrated to obtain the desired compound inquantitative yield.

Step B. 6-(1-Benzyl-piperidin-4-ylamino)-2,3-dihydro-indole-1-carboxylicacid tert-butyl ester

1-Benzyl-4-piperidone (1 mmol) was stirred with6-amino-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester (1.2mmol), Na(OAc)₃BH (1.3 mmol) and AcOH (1 mmol) in CH₂Cl₂ (20 mL). Theresulting mixture was stirred at 25° C. for 16 h. The mixture was washedwith satd. aq. NaHCO₃ (20 mL), and the organic layer was dried andconcentrated to provide the crude desired compound.

Step C.trans-6-[(1-Benzyl-piperidin-4-yl)-(3-phenyl-acryloyl)-amino]-2,3-dihydro-indole-1-carboxylicacid tert-butyl ester

To a solution of the product of Step B (1 mmol) in CH₂Cl₂ (10 mL) wasadded cinnamoyl chloride (1 mmol) and TEA (1.1 mmol). The resultingmixture was stirred at 25° C. for 16 h. The mixture was washed with satdaq. NaHCO₃ (20 mL), and the organic layer was dried and concentrated.After purification by silica gel chromatography, the desired compoundwas obtained (60%).

Step D

To a solution of the product of Step C (1 mmol) in CH₂Cl₂ (10 mL) wasadded TFA (1 mL). The mixture was stirred at 25° C. for 16 h. Afterconcentration, the title compound was obtained as its TFA salt inquantitative yield. ¹H NMR (500 MHz, CDCl₃): 9.78 (s, 1H), 7.65 (d,J=15.5 Hz, 1H), 7.46-7.23 (m, 12H), 7.08 (d, J=8.3 Hz, 1H), 6.13 (d,J=15.5 Hz, 1H), 4.99-4.95 (br m, 1H), 4.15-3.95 (m, 4H), 3.40-3.31 (m,4H), 3.02-2.88 (br m, 2H), 2.11-1.56 (m, 4H). MS: exact mass calculatedfor C₂₉H₃₁N₃O, 437.25; m/z found, 438.3 [M+H]⁺.

Example 3

trans-N-(1-Benzyl-piperidin-4-yl)-N-(1-formyl-2,3-dihydro-1H-indol-6-yl)-3-phenyl-acrylamide

To a solution of the compound prepared in Example 2 (24 mg, 0062 mmol)in acetonitrile (2 mL) was added formic acid (2.2 μL, 0.060 mmol) and1,1′-carbonyldiimidazole (11 mg, 0.060 mmol). The mixture was stirred at25° C. for 16 h. After concentration, the residue was purified by PTLC(20% EtOAc/CH₂Cl₂) to give the title compound (10 mg, 39%). ¹H NMR (500MHz, CDCl₃): 8.88 (s, 0.75H), 8.52 (s, 0.25H), 7.66 (d, J=15.6 Hz, 1H),7.33-7.21 (m, 12H), 6.78 (dd, J=6.2, 1.7 Hz, 1H), 6.14-6.11 (m, 1H),4.77-4.72 (m, 1H), 4.22-4.13 (m, 2H), 3.47-3.45 (m, 2H), 3.27-3.19 (m,2H), 3.00-2.82 (br m, 2H), 2.17-2.13 (br m, 2H), 1.84-1.78 (m, 2H),1.50-1.44 (m, 2H). MS: exact mass calculated for C₃₀H₃₁N₃O₂, 465.24; m/zfound, 466.2 [M+H]⁺.

Example 4

trans-N-(1-Benzyl-piperidin-4-yl)-N-[1-(3-oxo-butyryl)-2,3-dihydro-1H-indol-6-yl]-3-phenyl-acrylamide

To a solution of the compound prepared in Example 2 (41 mg, 0.092 mmol)in CH₂Cl₂ (3 mL) was added TEA (1.5 μL, 0.010 mmol) and diketene (8.1μL, 0.10 mmol). The mixture was stirred at 25° C. for 16 h. Afterconcentration, the residue was purified by PTLC (20% EtOAc/CH₂Cl₂) togive the title compound (26 mg, 53%). ¹H NMR (500 MHz, CDCl₃): 8.04 (s,1H), 7.65-7.61 (m, 1H), 7.30-7.16 (m, 12H), 6.79-6.72 (m, 1H), 6.18-6.11(m, 1H), 4.76-4.71 (m, 1H), 4.20-4.10 (m, 2H), 3.45 (s, 2H), 3.35-3.25(m, 2H), 2.95-2.85 (m, 2H), 2.34 (s, 3H), 2.25-2.10 (m, 2H), 2.00-1.85(br m, 1H), 1.85-1.75 (br m, 1H), 1.65-1.50 (m, 1H), 1.53-1.40 (m, 1H).MS: exact mass calculated for C₃₃H₃₅N₃O₃, 521.27; m/z found, 522.2[M+H]⁺.

Example 5

trans-{6-[(1-Benzyl-piperidin-4-yl)-(3-phenyl-acryloyl)-amino]-2,3-dihydro-indol-1-yl}-oxo-aceticacid ethyl ester

To a solution of the compound prepared in Example 2 (48 mg, 0.11 mmol)in CH₂Cl₂ (3 mL) was added pyridine (18 μL, 0.22 mmol),4-(dimethylamino)-pyridine (DMAP, 1.2 mg, 0.010 mmol), andchloro-oxo-acetic acid ethyl ester (25 μL, 0.22 mmol). The mixture wasstirred at 25° C. for 16 h. After concentration, the residue waspurified by PTLC (20% EtOAc/CH₂Cl₂) to give the title compound (15 mg,36%). ¹H NMR (500 MHz, CDCl₃): 8.04 (s, 1H), 7.64 (d, J=15.5 Hz, 1H),7.28-7.19 (m, 10H), 7.03 (dd, J=8.1, 1.8 Hz, 1H), 6.13 (d, J=15.5 Hz,1H), 4.75-4.72 (m, 1H), 4.40-4.32 (m, 4H), 3.45-3.44 (m, 2H), 3.28 (q,J=7.8 Hz, 2H), 2.94-2.82 (br m, 2H), 2.13 (t, J=7.8 Hz, 2H), 1.88-1.86(br m, 1H), 1.79-1.77 (br m, 1H), 1.59-1.48 (m, 1H), 1.43-1.38 (m, 4H).MS: exact mass calculated for C₃₃H₃₅N₃O₄, 537.26; m/z found, 538.3[M+H]⁺.

Example 6

trans-N-(1-Benzyl-piperidin-4-yl)-N-(1-methyl-2,3-dihydro-1H-indol-6-yl)-3-phenyl-acrylamideStep A. 1-Methyl-2,3-dihydro-1H-indol-6-ylamine

6-Nitroindoline (2 mmol) was combined with methyl iodide (2.2 mmol),n-Bu₄l (7.4 mg, 0.020 mmol), and K₂CO₃ (350 mg, 2.5 mmol) in acetone (10mL). The mixture was stirred at 25° C. for 16 h. The mixture waspartitioned between CH₂Cl₂ and satd. aq. NaHCO₃ (20 mL), and the organiclayer was dried and concentrated. Purification by silica gelchromatography provided 1-methyl-6-nitroindoline (300 mg, 84%). To asolution of 1-methyl-6-nitroindoline (194 mg, 1.15 mmol) in MeOH (2 mL)was added FeCl₃.6H₂O (3 mg), Me₂NNH₂ (0.80 mL, 11 mmol), and charcoal(25 mg). The mixture was heated at reflux for 4 h. The mixture wasfiltered through diatomaceous earth, and the filtrate was concentratedto provide the desired compound in quantitative yield.

Step B.(1-Benzyl-piperidin-4-yl)-(1-methyl-2,3-dihydro-1H-indol-6-yl)-amine

The product from Step A (161 mg, 1.1 mmol) was converted to the desiredcompound as in Example 2, Step B.

Step C.

The title compound (80 mg, 35%) was prepared as in Example 2, Step C. ¹HNMR (500 MHz, CDCl₃): 7.63 (d, J=15.5 Hz, 1H), 7.30-7.25 (m, 10H), 7.02(d, J=7.4 Hz, 1H), 6.38-6.36 (d, J=8.8 Hz, 1H), 6.25 (d, J=15.5 Hz, 1H),6.14 (s, 1H), 4.73-4.68 (m, 1H), 3.46-3.34 (m, 4H), 3.02-2.86 (m, 4H),2.73 (s, 3H), 2.17-2.12 (m, 2H), 1.86-1.77 (m, 2H), 1.61-1.51 (m, 2H).MS: exact mass calculated for C₃₀H₃₃N₃O, 451.26; m/z found, 452.2[M+H]⁺.

Example 7

trans-N-(1-Benzyl-piperidin-4-yl)-N-(1-methanesulfonyl-2,3-dihydro-1H-indol-6-yl)-3-phenyl-acrylamideStep A. 1-Methanesulfonyl-6-nitro-2,3-dihydro-1H-indole

To a solution of 6-nitroindoline (2 mmol) in CH₂Cl₂ (10 mL) was addedpyridine (180 μL, 2.2 mmol), DMAP (0.1 mmol), and methanesulfonylchloride (170 μL, 2.2 mmol). The resulting mixture was stirred at 25° C.for 16 h. The mixture was then washed with satd. aq. NaHCO₃ (20 mL), andthe organic layer was dried and concentrated. Purification by silica gelchromatography provided the desired compound (410 mg, 85%).

Step B. 1-Methanesulfonyl-2,3-dihydro-1H-indol-6-ylamine

To a solution of 1-methanesulfonyl-6-nitroindoline (240 mg, 1.0 mmol) inMeOH (2 mL) was added with FeCl₃.6H₂O (3 mg), Me₂NNH₂ (0.80 mL, 11mmol), and charcoal (25 mg). The mixture was heated at reflux for 4 h.After filtration through a pad of diatomaceous earth, the filtrate wasconcentrated to obtain the title compound in quantitative yield.

Step C.(1-Benzyl-piperidin-4-yl)-(1-methanesulfonyl-2,3-dihydro-1H-indol-6-yl)-amine

The crude title compound was prepared from the product from Step B (420mg, 1.1 mmol) as in Example 2, Step B.

Step D

The title compound (77 mg, 50%) was prepared from the product of Step Cas in Example 2, Step C. ¹H NMR (500 MHz, CDCl₃): 7.63 (d, J=15.5 Hz,1H), 7.29-7.18 (m, 12H), 6.73 (dd, J=8.3, 1.8 Hz, 1H), 6.10 (d, J=15.5Hz, 1H), 4.79-4.71 (m, 1H), 4.04 (q, J=9.3 Hz, 1H), 3.45 (s, 2H), 3.19(q, J=8.2 Hz, 1H), 2.91-2.89 (br m, 2H), 2.81 (s, 3H), 2.16-2.14 (br m,2H) 1.89-1.78 (br m, 2H), 1.55-1.40 (br m, 2H). MS: exact masscalculated for C₃₀H₃₃N₃O₃S, 515.22; m/z found, 516.3 [M+H]⁺.

Example 8

trans-N-(1-Benzyl-piperidin-4-yl)-3-phenyl-N-[1-(2,2,2-trifluoro-acetyl)-2,3-dihydro-1H-indol-6-yl]-acrylamide

To a solution of the compound prepared in Example 2 (48 mg, 0.11 mmol)in CH₂Cl₂ (3 mL) was added 1,3-dicyclohexylcarbodiimide (23 mg, 0.11mmol) and TFA (13 mg, 0.11 mmol). The mixture was stirred at 25° C. for16 h. After concentration, the residue was purified by PTLC (20%EtOAc/CH₂Cl₂) to give the title compound (24 mg, 41%). ¹H NMR (500 MHz,CDCl₃): 7.65 (d, J=15.5 Hz, 1H), 7.29-7.23 (m, 11H), 6.92-6.90 (d, J=8.5Hz, 1H), 6.12 (d, J=15.5 Hz, 1H), 4.79-4.74 (m, 1H), 4.38 (t, J=7.6 Hz,1H), 3.46 (s, 2H), 3.33 (q, J=7.8 Hz, 2H), 3.00-2.82 (br m, 2H), 2.14(t, J=11.4 Hz, 1H) 1.90-1.78 (m, 2H), 1.54-1.41 (m, 2H). MS: exact masscalculated for C₃₁H₃₀F₃N₃O₂, 533.58; m/z found, 534.2 [M+H]⁺.

Example 9

trans-N-(1-Acetyl-1,2,3,4-tetrahydro-quinolin-7-yl)-N-(1-benzyl-piperidin-4-yl)-3-phenyl-acrylamide Step A.7-Amino-3,4-dihydro-2H-quinoline-1-carboxylic acid tert-butyl ester

7-Nitro-1,2,3,4-tetrahydroquinoline (280 mg, 1.0 mmol) was converted tothe desired compound (100%) as in Example 2, Step A.

Step B.7-(1-Benzyl-piperidin-4-ylamino)-3,4-dihydro-2H-quinoline-1-carboxylicacid tert-butyl ester

The product from Step A (250 mg, 1.0 mmol) was converted to the desiredcompound (210 mg, 50%) as in Example 2, Step B.

Step C.N-(1-Benzyl-piperidin-4-yl)-3-phenyl-N-(1,2,3,4-tetrahydro-quinolin-7-yl)-acrylamide

The product from Step B (110 mg, 0.25 mmol) was converted to the desiredcompound (85 mg, 57%) as in Example 2, Step C.

Step D.N-(1-Acetyl-1,2,3,4-tetrahydro-quinolin-7-yl)-N-(1-benzyl-piperidin-4-yl)-3-phenyl-acrylamide

The desired compound (100%) was obtained as its TFA salt from theproduct of Step C (85 mg) as in Example 2, Step D.

Step E

To a solution of the product from Step D (25 mg, 0.044 mmol) in CH₂Cl₂(10 mL) was added pyridine (7.0 μL, 0.090 mmol), DMAP (0.5 mg, 4 μmol),and acetyl chloride (6.3 μL, 0.089 mmol). The mixture was stirred at 25°C. for 16 h. After concentration, the residue was purified by PTLC (20%EtOAc/CH₂Cl₂) to give the title compound (11 mg, 50%). ¹H NMR (500 MHz,CDCl₃): 7.64 (d, J=15.5 Hz, 1H), 7.35-7.17 (m, 12H), 6.88-6.87 (br m,1H), 6.13 (d, J=15.5 Hz, 1H), 4.77-4.72 (m, 1H), 3.92-3.80 (m, 1H),3.80-3.69 (m, 1H), 3.49 (s, 2H), 2.94-2.92 (br m, 2H), 2.85-2.75 (br m,2H), 2.24-2.10 (br m, 5H), 2.04-1.99 (m, 2H), 1.88-1.75 (br m, 2H),1.58-1.44 (br m, 2H). MS: exact mass calculated for C₃₂H₃₅N₃O₂, 493.27;m/z found, 494.2 [M+H]⁺.

Example 10

trans-N-(1-Benzyl-piperidin-4-yl)-N-(2-oxo-2,3-dihydro-1H-indol-6-yl)-3-phenyl-acrylamideStep A. 6-Nitro-1,3-dihydro-indol-2-one

To a solution of (2,4-dinitrophenyl)-acetic acid methyl ester (5 mmol)in 50 mL of ethanol was added a suspension of 10% Pd/C (0.12 g) inethanol/dimethoxyethane (1:1). The mixture was hydrogenated at 50 psiuntil hydrogen uptake ceased. The mixture was filtered to remove thecatalyst, and the filtrate was concentrated. The residue was dilutedwith 10 mL of 1 M HCl and heated at reflux for 20 min. The mixture wascooled to rt, neutralized with 1 M NaOH to pH 7, and extracted withEtOAc (3×). The organic layers were combined, dried over Na₂SO₄, andconcentrated to give the desired compound as a semi-solid, which wasused directly in the next step.

Step B

The title compound (75 mg, 31%) was prepared from the product of Step Aas in Example 2, Steps B and C. ¹H NMR (500 MHz, CDCl₃): 9.39 (s, 1H),7.65 (d, J=15.5 Hz, 1H), 7.32-7.14 (m, 10H), 7.04 (t, J=7.0 Hz, 1H),6.71 (dd, J=7.8, 1.6 Hz, 1H), 6.14 (br s, 1H), 6.06 (d, J=15.5 Hz, 1H),4.85-4.72 (m, 1H), 3.59-3.30 (m, 4H), 3.06-3.04 (br m, 1H), 2.85-2.83(br m, 1H), 2.23-2.09 (m, 2H), 1.83-1.57 (m, 4H). MS: exact masscalculated for C₂₉H₂₉N₃O₂, 451.23; m/z found, 452.2 [M+H]⁺.

Example 11

trans-N-(1-Acetyl-1H-indol-6-yl)-N-(1-benzyl-piperidin-4-yl)-3-phenyl-acrylamideStep A. 1H-Indol-6-ylamine

The desired compound (100%) was prepared from 6-nitroindole (650 mg, 4.0mmol) as in Example 7, Step B.

Step B. (1-Benzyl-piperidin-4-yl)-(1H-indol-6-yl)-amine

The desired compound (756 mg, 62%) was prepared from the product fromStep A (530 mg, 4.0 mmol) as in Example 2, Step B.

Step C.trans-N-(1-Benzyl-piperidin-4-yl)-N-(1H-indol-6-yl)-3-phenyl-acrylamide

The desired compound (135 mg, 62%) was prepared from the product fromStep B (150 mg, 0.50 mmol) as in Example 2, Step C.

Step D

To a solution of the product from Step C (80 mg, 0.2 mmol) in THF (20mL) was added NaH (95%, 8.8 mg, 0.37 mmol). After 10 min, acetylchloride (26 μL, 0.37 mmol) was added. The resulting mixture was stirredat 25° C. for 16 h. After concentration, the residue was purified byPTLC (20% EtOAc/CH₂Cl₂) to give the title compound (35 mg, 41%). ¹H NMR(500 MHz, CDCl₃): 7.63 (d, J=15.6 Hz, 1H), 7.57 (d, J=8.1 Hz, 1H), 7.52(d, J=3.4 Hz, 1H), 7.34-7.12 (m, 11H), 7.03 (d, J=8.7 Hz, 1H), 6.71 (d,J=3.4 Hz, 1H), 6.09 (d, J=15.6 Hz, 1H), 4.81-4.78 (m, 1H), 3.44 (s, 2H),2.91-2.87 (m, 2H), 2.65 (s, 3H), 2.20-2.05 (m, 1H), 1.94-1.92 (br m,1H), 1.83-1.81 (br m, 1H), 1.57-1.41 (m, 3H). MS: exact mass calculatedfor C₃₁H₃₁N₃O₂, 477.24; m/z found, 478.3 [M+H]⁺.

Example 12

N-(1-Acetyl-2,3-dihydro-1H-indol-6-yl)-N-(1-benzyl-piperidin-4-yl)-3-phenyl-propionamide

trans-N-(1-Acetyl-2,3-dihydro-1H-indol-6-yl)-N-(1-benzyl-piperidin-4-yl)-3-phenyl-acrylamide(Example 1, 0.6 g, 1 mmol) was dissolved in 50 mL of MeOH and 20%Pd(OH)₂/C (21 mg) was added in portions over the course of the reaction.The mixture was shaken in a Parr hydrogenator at ˜50 psi overnight. Themixture was filtered through a pad of diatomaceous earth. The filtratewas concentrated to yield the crude product contaminated withde-benzylated material. The mixture was purified by reverse-phase HPLCto yield the desired product as its TFA salt as a light pink powder(0.06 g, 8%). ¹H NMR (400 MHz, DMSO-d₆): 9.13 (br s, 1H), 7.80 (s, 1H),7.45 (s, 5H), 7.32-7.09 (m, 4H), 7.06 (d, J=9.1 Hz, 2H), 6.69 (dd,J=6.3, 2.4 Hz, 1H), 4.78-4.62 (m, 1H), 4.23 (d, J=9.2 Hz, 2H), 4.12 (q,J=8.8 Hz, 2H), 3.39-3.23 (m, 2H), 3.23-3.01 (m, 4H), 2.77 (t, J=8.7 Hz,2H), 2.25-2.02 (m, 5H), 1.97-1.80 (m, 2H), 1.65-1.33 (m, 2H). MS: exactmass calculated for C₃₁H₃₅N₃O₂, 481.27; m/z found, 482.3 [M+H]⁺.

Example 13

trans-2-Phenyl-cyclopropanecarboxylic acid(1-acetyl-2,3-dihydro-1H-indol-6-yl)-(1-benzyl-piperidin-4-yl)-amide

To a solution of1-[6-(1-benzyl-piperidin-4-ylamino)-2,3-dihydro-indol-1-yl]-ethanone(0.353 g, 1.01 mmol) in 50 mL of acetonitrile was addeddiisopropylethylamine (0.193 mL, 1.11 mmol) andtrans-2-phenyl-1-cyclopropanecarbonyl chloride (90%, 0.174 mL, 1.01mmol). The reaction mixture was stirred overnight, and then was filteredthrough diatomaceous earth. The filtrate was evaporated and the residuewas chromatographed over silica gel (acetone/MeOH/CH₂Cl₂) to provide thedesired product as a tan solid (0.30 g, 61%). ¹H NMR (400 MHz, CDCl₃):8.04 (s, 1H), 7.38-6.98 (m, 9H), 6.97-6.82 (m, 2H), 6.76 (dd, J=12.5,6.2 Hz, 1H), 4.65 (br t, J=12.7 Hz, 1H), 4.12 (t, J=9.5 Hz, 1H),4.09-3.87 (m, 1H), 3.44 (s, 2H), 3.26-3.07 (m, 2H), 2.97-2.79 (m, 2H),2.51-2.47 (m, 1H), 2.29-1.98 (m, 5H), 1.92-1.66 (m, 2H), 1.65-1.29 (m,4H), 1.08-0.96 (m, 1H). MS: exact mass calculated for C₃₂H₃₅N₃O₂,493.27; m/z found, 494.3 [M+H]⁺.

Example 14

trans-1-{6-[(1-Benzyl-piperidin-4-yl)-(3-phenyl-allyl)-amino]-2,3-dihydro-indol-1-yl}-ethanone

1-[6-(1-Benzyl-piperidin-4-ylamino)-2,3-dihydro-indol-1-yl]-ethanone(0.357 g, 1.02 mmol) was dissolved in acetonitrile (50 mL) withstirring. Cinnamyl bromide (0.212 g, 1.08 mmol) was added and thereaction was stirred for 3 days. Concentration of the reaction mixturegave a residue that was chromatographed using reverse-phase HPLC toprovide the TFA salt of the desired product as a tan powder (0.183 g,31%). LC/MS analysis showed a nearly 1:1 mixture of products, bothshowing the correct molecular ion. MS: 5 exact mass calculated forC₃₁H₃₅N₃O, 465.28; m/z found, 466.3 [M+H]⁺.

Example 15

trans-2-Phenyl-ethenesulfonic acid(1-acetyl-2,3-dihydro-1H-indol-6-yl)-(1-benzyl-piperidin-4-yl)-amide

A mixture of1-[6-(1-benzyl-piperidin-4-ylamino)-2,3-dihydro-indol-1-yl]-ethanone(0.10 g, 0.29 mmol), 2-phenyl-ethenesulfonyl chloride (87 mg, 0.43mmol), and TEA (0.08 mL, 0.57 mmol) in CH₂Cl₂ (5 mL) was stirred at rtfor 20 h. The reaction mixture was concentrated, and the residue waspurified on silica gel (60-70% EtOAc/hexanes) to afford the titlecompound (138 mg, 92%).

¹H NMR (500 MHz, CDCl₃): 8.12 (s, 1H), 7.50-7.48 (m, 2H), 7.43 (s, 1H),7.41-7.39 (m, 3H), 7.25 (d, J=6.8 Hz, 2H), 7.20 (t, J=7.0 Hz, 3H), 7.15(d, J=7.9 Hz, 1H), 6.91 (d, J=7.8 Hz, 1H), 6.86 (d, J=15.0 Hz, 1H), 4.13(t, J=8.0 Hz, 2H), 3.98-3.40 (m, 1H), 3.41 (s, 2H), 3.20 (t, J=8.5 Hz,2H), 2.87 (d, J=10.5 Hz, 2H), 2.20 (s, 3H), 2.06-2.02 (m, 2H), 1.88 (d,J=10.7 Hz, 2H), 1.61-1.55 (m, 2H). MS: exact mass calculated forC₃₀H₃₃N₃O₃S, 515.22; m/z found, 516.3 [M+H]⁺.

Example 16

3-Phenyl-propynoic acid(1-acetyl-2,3-dihydro-1H-indol-6-yl)-(1-benzyl-piperidin-4-yl)-amide

A mixture of phenyl-propynoic acid (220 mg, 1.5 mmol) and thionylchloride (3.0 mL) in toluene (3.0 mL) was heated at reflux for 4 h. Thereaction mixture was cooled to rt and the excess thionyl chloride andtoluene were removed under reduced pressure. The resulting crude acidchloride was dissolved in CH₂Cl₂ (5 mL) and treated with1-[6-(1-benzyl-piperidin-4-ylamino)-2,3-dihydro-indol-1-yl]-ethanone(349 mg, 1.0 mmol) and TEA (0.28 mL, 2.0 mmol) at rt for 20 h. Thereaction mixture was concentrated, and the residue was purified onsilica gel (60-70% EtOAc/hexanes) to afford the title compound (402 mg,84%). ¹H NMR (500 MHz, CDCl₃): 8.12 (s, 1H), 7.28-7.18 (m, 9H), 7.09 (d,J=7.8 Hz, 2H), 6.86 (dd, J=8.0, 1.7 Hz, 1H), 4.65-4.59 (m, 1H), 4.13 (t,J=8.5 Hz, 2H), 3.44 (s, 2H), 3.24 (t, J=8.5 Hz, 2H), 2.89 (d, J=10.7 Hz,2H), 2.22 (s, 3H), 2.10 (t, J=10.8 Hz, 2H), 1.90-1.78 (m, 2H), 1.63-1.58(m, 2H). MS: exact mass calculated for C₃₁H₃₁N₃O₂, 477.24; m/z found,478.3 [M+H]⁺.

Example 17

cis-N-(1-Acetyl-2,3-dihydro-1H-indol-6-yl)-N-(1-benzyl-piperidin-4-yl)-3-phenyl-acrylamideStep A.{[(1-Acetyl-2,3-dihydro-1H-indol-6-yl)-(1-benzyl-piperidin-4-yl)-carbamoyl]-methyl}-phosphonicacid bis-(2,2,2-trifluoro-ethyl)ester

A mixture of1-[6-(1-benzyl-piperidin-4-ylamino)-2,3-dihydro-indol-1-yl]-ethanone(0.50 g, 1.4 mmol) and [bis-(2,2,2-trifluoro-ethoxy)-phosphoryl]-aceticacid methyl ester (910 mL, 4.3 mmol) was dissolved in 10 mL of xylenesand heated at reflux for 12 h. The mixture was concentrated in vacuo andthe residue was purified by silica gel chromatography (EtOAc) to afford468 mg (52%) of the desired intermediate as a yellow foam. ¹H NMR (500MHz, CDCl₃): 7.97 (br s, 1H), 7.27-7.19 (m, 6H), 6.76-6.74 (m, 1H),4.56-4.38 (m, 4H), 4.16-4.12 (m, 2H), 3.42 (s, 2H), 3.27-3.22 (m, 2H),2.91-2.86 (m, 4H), 2.24 (s, 3H), 2.09-2.04 (m, 2H), 1.80-1.73 (m, 2H),1.60 (br s, 1H), 1.47-1.39 (m, 2H). MS: exact mass calculated forC₂₈H₃₂F₆N₃O₅P, 635.20; m/z found, 636.2 [M+H]⁺, 658.2 [M+Na]⁺.

Step B

To a mixture of the product of Step A (0.100 g, 0.157 mmol) and18-crown-6 (208 mg, 0.787 mmol) in 1 mL of THF at −78° C. was added 314μL of potassium bis(trimethylsilyl)amide (0.5 M in toluene) followed bybenzaldehyde (16 mL, 0.157 mmol). After 30 min, the reaction wasquenched by the addition of satd. aq. NH₄Cl and EtOAc. The organic layerwas separated, dried over Na₂SO₄, filtered, and concentrated in vacuo.The crude material was purified by PTLC (70% EtOAc/hexanes) to afford 57mg (75%) of the title compound as a white foam. ¹H NMR (500 MHz, CDCl₃):7.90 (s, 1H), 7.40 (d, J=5.0 Hz, 2H), 7.32-7.19 (m, 8H), 6.96 (d, J=6.9Hz, 1H), 6.36 (d, J=8.7 Hz, 1H), 6.28 (d, J=12.5 Hz, 1H), 5.78 (d,J=12.5 Hz, 1H), 4.67 (br s, 1H), 4.11-4.07 (m, 2H), 3.43 (s, 2H), 3.18(br s, 2H), 2.87-2.85 (m, 2H), 2.20 (s, 3H), 2.13-2.08 (m, 2H), 1.79 (brs, 2H), 1.43 (br s, 2H). MS: exact mass calculated for C₃₁H₃₃N₃O₂,479.26; m/z found, 480.2 [M+H]⁺, 502.3 [M+Na]⁺.

Example 18

trans,trans-5-Phenyl-penta-2,4-dienoic acid(1-acetyl-2,3-dihydro-1H-indol-6-yl)-(1-benzyl-piperidin-4-yl)-amideStep A.{[(1-Acetyl-2,3-dihydro-1H-indol-6-yl)-(1-benzyl-piperidin-4-yl)-carbamoyl]-methyl}-phosphonicacid diethyl ester

A mixture of1-[6-(1-benzyl-piperidin-4-ylamino)-2,3-dihydro-indol-1-yl]-ethanone(2.5 g, 7.16 mmol), methyl diethylphosphonoacetate (4.0 mL, 21 mmol) andcatalytic DMAP was suspended in 36 mL of m-xylenes and heated at refluxfor 48 h. The solution was concentrated in vacuo and the residue waspurified by silica gel chromatography (5% MeOH/EtOAc) to afford 2.5 g(65%) of the desired intermediate. ¹H NMR (500 MHz, CDCl₃): 7.97 (br s,1H), 7.27-7.15 (m, 6H), 6.80-6.79 (m, 1H), 4.62-4.60 (m, 1H), 4.21-4.06(m, 6H), 3.41 (s, 2H), 3.23-3.20 (m, 2H), 2.84 (br s, 2H), 2.74-2.70 (m,2H), 2.22 (s, 3H), 2.08-2.04 (m, 2H), 1.81-1.72 (m, 2H), 1.48-1.26 (m,7H). MS: exact mass calculated for C₂₈H₃₈N₃O₅P, 527.25; m/z found, 528.3[M+H]⁺, 550.2 [M+Na]⁺.

Step B

To a mixture of the product of Step A (157 mg, 0.309 mmol) and LiCl(62.5 mg, 1.48 mmol) in 3.5 mL of acetonitrile was added1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 40.4 μL, 0.324 mmol) followedby 3-phenyl-propenal (43 μL, 0.34 mmol). The mixture was stirred at rtfor 12 h and then was diluted with satd. aq. NH₄C₁ and CH₂Cl₂. Theorganic layer was separated and washed with brine, dried over Na₂SO₄,filtered and concentrated in vacuo. Purification by silica gelchromatography (60% EtOAc/hexanes) afforded 125 mg (80%) of the titlecompound. ¹H NMR (500 MHz, CDCl₃): 8.01 (s, 1H), 7.41-7.17 (m, 10H),6.80-6.60 (m, 5H), 5.74-5.71 (m, 1H), 4.73-3.68 (m, 1H), 4.16-4.11 (m,2H), 3.44 (br s, 2H), 3.28-3.23 (m, 2H), 2.88 (br s, 2H), 2.23 (s, 3H),2.14-2.10 (m, 2H), 1.86-1.76 (m, 2H), 1.63-1.42 (m, 2H).

Example 19

N-(1-Acetyl-2,3-dihydro-1H-indol-6-yl)-N-(1-benzyl-piperidin-4-yl)-acrylamide

The title compound (0.34 g, 83%), obtained as a pale yellow glassysolid, was prepared from1-[6-(1-benzyl-piperidin-4-ylamino)-2,3-dihydro-indol-1-yl]-ethanone(0.350 g, 1.00 mmol) and acryloyl chloride (0.080 mL, 1.0 mmol) as inExample 13. ¹H NMR (300 MHz, CDCl₃): 7.98 (s, 1H), 7.34-7.12 (m, 6H),6.72 (dd, J=9.1, 2.2 Hz, 1H), 6.31 (dd, J=15.3, 2.2 Hz, 1H), 5.88 (dd,J=12.5, 10.1 Hz, 1H), 5.43 (dd, J=10.1, 2.2 Hz, 1H), 4.77-4.61 (m, 1H),4.13 (t, J=8.6 Hz, 2H), 3.44 (s, 2H), 3.24 (t, J=9.4 Hz, 2H), 2.88 (brd, J=10.2 Hz, 2H), 2.23 (s, 3H), 2.12 (t, J=12.5 Hz, 2H), 1.90-1.70 (brm, 2H), 1.60-1.35 (br m, 2H). MS: exact mass calculated for C₂₅H₂₉N₃O₂,403.23; m/z found, 404.3 [M+H]⁺.

Example 20

trans-N-(1-Acetyl-2,3-dihydro-1H-indol-6-yl)-N-(1-benzyl-piperidin-4-yl)-3-thiophen-3-yl-acrylamide

To a mixture of trans-3-thiophen-3-yl-acrylic acid (66 mg, 0.43 mmol)and oxalyl chloride (45 μL, 0.52 mmol) in 2 mL of CH₂Cl₂ was added acatalytic amount of DMF. After stirring at rt for 2 h, the mixture wasconcentrated in vacuo. The resulting crude acid chloride was dissolvedin CH₂Cl₂ and treated with TEA (80 μL, 0.58 mmol) and1-[6-(1-benzyl-piperidin-4-ylamino)-2,3-dihydro-indol-1-yl]-ethanone(0.100 g, 0.286 mmol). After stirring for 4 h, the mixture was washedwith satd. aq. NaHCO₃ followed by brine. The organic layer was driedover Na₂SO₄, filtered, and concentrated in vacuo. Purification by silicagel chromatography (60% EtOAc/hexanes) afforded 118 mg (64%) of thetitle compound. ¹H NMR (500 MHz, CDCl₃): 8.02 (br s, 1H), 7.83 (d,J=15.7 Hz, 1H), 7.39-7.16 (m, 8H), 6.94-6.93 (m, 1H), 6.73-6.72 (m, 1H),5.97 (d, J=15.7 Hz, 1H), 4.74-4.70 (m, 1H), 4.17-4.13 (m, 2H), 3.45 (brs, 2H), 3.28-3.23 (m, 2H), 2.88 (br s, 3H), 2.23 (s, 3H), 2.13 (m, 2H),1.88-1.76 (m, 3H). MS: exact mass calculated for C₂₉H₁₈N₃O₂, 485.21; m/zfound, 486.2 [M+H]⁺, 508.1 [M+Na]⁺.

Example 21

trans-N-(1-Acetyl-2,3-dihydro-1H-indol-6-yl)-N-(1-benzyl-piperidin-4-yl)-3-pyridin-2-yl-acrylamide

The title compound (186 mg, 88%) was as in Example 18 usingpyridine-2-carbaldehyde in place of 3-phenyl-propenal. ¹H NMR (500 MHz,CDCl₃): 8.47 (br s, 1H), 8.04 (s, 1H), 7.65-7.57 (m, 2H), 7.31-7.11 (m,8H), 6.76-6.74 (m, 1H), 6.67 (d, J=15.3 Hz, 1H), 4.76-4.71 (m, 1H),4.15-4.11 (m, 2H), 3.44 (s, 2H), 3.26-3.22 (m, 2H), 2.89 (br s, 2H),2.21 (s, 3H), 2.15-2.10 (m, 2H), 1.90-1.76 (m, 2H), 1.62-1.42 (m, 2H).MS: exact mass calculated for C₃₀H₃₂N₄O₂, 480.25; m/z found, 481.2[M+H]⁺, 503.2 [M+Na]⁺.

Example 22

trans-N-(1-Acetyl-2,3-dihydro-1H-indol-6-yl)-N-(1-benzyl-piperidin-4-yl)-3-pyridin-3-yl-acrylamide

The title compound (184 mg, 85%) was prepared as in Example 18 usingpyridine-3-carbaldehyde in place of 3-phenyl-propenal. ¹H NMR (500 MHz,CDCl₃): 8.55-8.44 (m, 2H), 8.04 (s, 1H), 7.60-7.53 (m, 2H), 7.28-7.17(m, 7H), 6.75-6.73 (m, 1H), 6.23 (d, J=15.8 Hz, 1H), 4.74-4.69 (m, 1H),4.18-4.13 (m, 2H), 3.44 (br s, 2H), 3.29-3.24 (m, 2H), 2.89 (br s, 2H),2.23 (s, 3H), 2.15-2.10 (m, 2H), 1.88-1.78 (m, 2H), 1.55-1.44 (m, 2H).MS: exact mass calculated for C₃₀H₃₂N₄O₂, 480.25; m/z found, 481.2[M+H]⁺, 503.2 [M+Na]⁺.

Example 23

trans-N-(1-Acetyl-2,3-dihydro-1H-indol-6-yl)-N-(1-benzyl-piperidin-4-yl)-3-pyridin-4-yl-acrylamide

The title compound (190 mg, 90%) was prepared as in Example 18 usingpyridine-4-carbaldehyde in place of 3-phenyl-propenal. ¹H NMR (500 MHz,CDCl₃): 8.50-8.49 (m, 2H), 8.04 (s, 1H), 7.53 (d, J=15.5 Hz, 1H),7.30-7.18 (m, 6H), 7.10-7.09 (m, 2H), 6.74-6.73 (m, 1H), 6.31 (d, J=15.5Hz, 1H), 4.73-4.68 (m, 1H), 4.18-4.14 (m, 2H), 3.44 (s, 2H), 3.30-3.25(m, 2H), 2.89 (br s, 2H), 2.24 (s, 3H), 2.15-2.10 (m, 2H), 1.88-1.77 (m,2H), 1.54-1.43 (m, 2H).

MS: exact mass calculated for C₃₀H₃₂N₄O₂, 480.25; m/z found, 481.2[M+H]⁺, 503.2 [M+Na]⁺.

Example 24

trans-N-(1-Acetyl-2,3-dihydro-1H-indol-6-yl)-N-(1-benzyl-piperidin-4-yl)-3-(1-oxy-pyridin-4-yl)-acrylamide

The title compound (194 mg, 89%) was prepared as in Example 18 using1-oxy-pyridine-4-carbaldehyde in place of 3-phenyl-propenal. ¹H NMR (500MHz, CDCl₃): 8.04-8.03 (m, 3H), 7.47 (d, J=15.5 Hz, 1H), 7.30-7.19 (m,6H), 7.10-7.09 (m, 2H), 6.74-6.73 (m, 1H), 6.18 (d, J=15.5 Hz, 1H), 4.69(br s, 1H), 4.18-4.14 (m, 2H), 3.44 (s, 2H), 3.30-3.25 (m, 2H), 2.88 (brs, 2H), 2.24 (s, 3H), 2.14-2.10 (m, 2H), 1.87-1.76 (m, 2H), 1.54-1.42(m, 2H). MS: exact mass calculated for C₃₀H₃₂N₄O₃, 496.25; m/z found,497.2 [M+H]⁺, 519.2 [M+Na]⁺.

Example 25

trans-N-(1-Acetyl-2,3-dihydro-1H-indol-6-yl)-N-(1-benzyl-piperidin-4-yl)-3-(1H-imidazol-2-yl)-acrylamide

The title compound (154 mg, 75%) was prepared as in Example 18 using1H-imidazole-2-carbaldehyde in place of 3-phenyl-propenal. ¹H NMR (500MHz, CDCl₃): 7.98 (br s, 1H), 7.73 (d, J=15.3 Hz, 1H), 7.28-7.19 (m,5H), 7.00-6.91 (m, 3H), 6.66-6.65 (m, 1H), 6.34 (d, J=15.3 Hz, 1H),4.63-4.58 (m, 1H), 4.16-4.04 (m, 2H), 3.44 (s, 2H), 3.21-3.12 (m, 2H),2.91 (br s, 2H), 2.17 (s, 3H), 2.11-2.06 (m, 2H), 1.90-1.77 (m, 2H),1.56-1.54 (m, 2H). MS: exact mass calculated for C₂₈H₃₁N₅O₂, 469.58; m/zfound, 470.2 [M+H]⁺, 492.2 [M+Na]⁺.

Example 26

trans-N-(1-Acetyl-2,3-dihydro-1H-indol-6-yl)-N-(1-benzyl-piperidin-4-yl)-3-(4-trifluoromethyl-phenyl)-acrylamide

The title compound (49.5 mg, 32%) was prepared as in Example 20 usingtrans-3-(4-trifluoromethyl-phenyl)-acrylic acid in place oftrans-3-thiophen-3-yl-acrylic acid. ¹H NMR (500 MHz, CDCl₃): 8.04 (s,1H), 7.62 (d, J=15.5 Hz, 1H), 7.50-7.49 (m, 2H), 7.36-7.34 (m, 2H),7.31-7.18 (m, 6H), 6.75-6.73 (m, 1H), 6.22 (d, J=15.5 Hz, 1H), 4.74-4.69(m, 1H), 4.17-4.10 (m, 2H), 3.47 (s, 2H), 3.29-3.24 (m, 2H), 2.91 (br s,2H), 2.23 (s, 3H), 2.19-2.13 (m, 2H), 1.89-1.78 (m, 2H), 1.57-1.45 (m,2H). MS: exact mass calculated for C₃₂H₃₂F₃N₃O₂, 547.24; m/z found,548.3 [M+H]⁺, 570.2 [M+Na]⁺.

Example 27

trans-N-(1-Acetyl-2,3-dihydro-1H-indol-6-yl)-N-(1-benzyl-piperidin-4-yl)-3-(3-trifluoromethyl-phenyl)-acrylamide

The title compound (80.7 mg, 52%) was prepared as in Example 20 usingtrans-3-(3-trifluoromethyl-phenyl)-acrylic acid in place oftrans-3-thiophen-3-yl-acrylic acid. ¹H NMR (500 MHz, CDCl₃): 8.05 (s,1H), 7.63 (d, J=15.5 Hz, 1H), 7.50-7.36 (m, 5H), 7.30-7.18 (m, 6H),6.75-6.74 (m, 1H), 6.19 (d, J=15.5 Hz, 1H), 4.74-4.70 (m, 1H), 4.18-4.11(m, 2H), 3.45 (s, 2H), 3.30-3.24 (m, 2H), 2.89 (br s, 2H), 2.24 (s, 3H),2.15-2.11 (m, 2H), 1.89-1.77 (m, 2H), 1.56-1.43 (m, 2H). MS: exact masscalculated for C₃₂H₃₂F₃N₃O₂, 547.24; m/z found, 548.3 [M+H]⁺, 570.2[M+Na]⁺.

Example 28

trans-N-(1-Acetyl-2,3-dihydro-1H-indol-6-yl)-N-(1-benzyl-piperidin-4-yl)-3-(2-trifluoromethyl-phenyl)-acrylamide

The title compound (144 mg, 92%) was prepared as in Example 20 usingtrans-3-(2-trifluoromethyl-phenyl)-acrylic acid in place oftrans-3-thiophen-3-yl-acrylic acid. ¹H NMR (500 MHz, CDCl₃): 8.05 (s,1H), 8.00-7.97 (m, 1H), 7.61-7.59 (m, 1H), 7.38-7.15 (m, 9H), 6.74-6.73(m, 1H), 6.13 (d, J=15.3 Hz, 1H), 4.75-4.70 (m, 1H), 4.14-4.09 (m, 2H),3.44 (s, 2H), 3.23 (br s, 2H), 2.89 (br s, 2H), 2.22 (s, 3H), 2.14-2.09(m, 2H), 1.90-1.77 (m, 2H), 1.58-1.42 (m, 2H). MS: exact mass calculatedfor C₃₂H₃₂F₃N₃O₂, 547.24; m/z found, 548.3 [M+H]⁺, 570.2 [M+Na]⁺.

Example 29

trans-N-(1-Acetyl-2,3-dihydro-1H-indol-6-yl)-N-(1-benzyl-piperidin-4-yl)-3-(3-bromo-phenyl)-acrylamide

The title compound (134 mg, 84%) was prepared as in Example 20 usingtrans-3-(3-bromo-phenyl)-acrylic acid in place oftrans-3-thiophen-3-yl-acrylic acid.

¹H NMR (500 MHz, CDCl₃): 8.04 (s, 1H), 7.54 (d, J=15.5 Hz, 1H),7.37-7.35 (m, 2H), 7.28-7.10 (m, 9H), 6.13 (d, J=15.5 Hz, 1H), 4.74-4.69(m, 1H), 4.20-4.09 (m, 2H), 3.44 (s, 2H), 3.29-3.23 (m, 2H), 2.90-2.87(m, 2H), 2.21 (s, 3H), 2.14-2.10 (m, 2H), 1.88-1.76 (m, 2H), 1.55-1.42(m, 2H). MS: exact mass calculated for C₃₁H₃₂BrN₃O₂, 557.17; m/z found,560.2 [M+H]⁺.

Example 30

trans-N-(1-Acetyl-2,3-dihydro-1H-indol-6-yl)-N-(1-benzyl-piperidin-4-yl)-3-(3-fluoro-phenyl)-acrylamide

The title compound (94 mg, 66%) was prepared as in Example 20 usingtrans-3-(3-fluoro-phenyl)-acrylic acid in place oftrans-3-thiophen-3-yl-acrylic acid. ¹H NMR (500 MHz, CDCl₃): 8.04 (s,1H), 7.58 (d, J=15.5 Hz, 1H), 7.30-7.17 (m, 8H), 7.06-7.05 (m, 1H),6.96-6.92 (m, 1H), 6.74-6.73 (m, 1H), 6.14 (d, J=15.5 Hz, 1H), 4.74 (m,1H), 4.19-4.11 (m, 2H), 3.44 (s, 2H), 3.31-3.24 (m, 2H), 2.91-2.87 (m,2H), 2.25 (s, 3H), 2.15-2.10 (m, 2H), 1.88-1.76 (m, 2H), 1.55-1.43 (m,2H). MS: exact mass calculated for C₃₁H₃₂FN₃O₂, 497.25; m/z found, 498.2[M+H]⁺, 520.2 [M+Na]⁺.

Example 31

trans-N-(1-Acetyl-2,3-dihydro-1H-indol-6-yl)-N-(1-benzyl-piperidin-4-yl)-3-(3-chloro-phenyl)-acrylamide

The title compound (71 mg, 48%) was prepared as in Example 20 usingtrans-3-(3-chloro-phenyl)-acrylic acid in place oftrans-3-thiophen-3-yl-acrylic acid.

¹H NMR (500 MHz, CDCl₃): 8.04 (s, 1H), 7.56 (d, J=15.5 Hz, 1H),7.28-7.14 (m, 10H), 6.74-6.72 (m, 1H), 6.14 (d, J=15.5 Hz, 1H),4.74-4.69 (m, 1H), 4.19-4.13 (m 2H), 3.44 (s, 2H), 3.31-3.24 (m, 2H),2.91-2.87 (m, 2H), 2.24 (s, 3H), 2.15-2.10 (m, 2H), 1.89-1.76 (m, 2H),1.56-1.42 (m, 2H). MS: exact mass calculated for C₃₁H₃₂ClN₃O₂, 513.22;m/z found, 514.2 [M+H]⁺, 536.2 [M+Na]⁺.

Example 32

trans-N-(1-Acetyl-2,3-dihydro-1H-indol-6-yl)-N-(1-benzyl-piperidin-4-yl)-3-m-tolyl-acrylamide

The title compound (112 mg, 78%) was prepared as in Example 20 usingtrans-3-m-tolyl-acrylic acid in place of trans-3-thiophen-3-yl-acrylicacid. ¹H NMR (500 MHz, CDCl₃): 8.05 (s, 1H), 7.60 (d, J=15.5 Hz, 1H),7.28-7.18 (m, 5H), 7.16 (d, J=7.8 Hz, 1H), 7.12 (d, J=7.1 Hz, 1H), 6.74(d, J=7.9 Hz, 1H), 6.12 (d, J=15.5 Hz, 1H), 4.76-4.71 (m, 1H), 4.16-4.11(m, 2H), 3.44 (s, 2H), 3.28-3.23 (m, 2H), 2.90-2.85 (m, 2H), 2.28 (s,3H), 2.23 (s, 3H), 2.12 (t, J=11.4 Hz, 2H), 1.89-1.87 (m, 1H), 1.78-1.76(m, 1H), 1.55-1.53 (m, 1H), 1.44-1.41 (m, 1H). MS: exact mass calculatedfor C₃₂H₃₅N₃O₂, 493.27; m/z found, 494.2 [M+H]⁺.

Example 33

trans-N-(1-Acetyl-2,3-dihydro-1H-indol-6-yl)-N-(1-benzyl-piperidin-4-yl)-3-(3-nitro-phenyl)-acrylamide

The title compound (118 mg, 79%) was prepared as in Example 20 usingtrans-3-(3-nitro-phenyl)-acrylic acid in place oftrans-3-thiophen-3-yl-acrylic acid. ¹H NMR (500 MHz, CDCl₃): 8.10-8.05(m, 2H), 7.65 (d, J=15.5 Hz, 1H), 7.58-7.57 (m, 1H), 7.46-7.43 (m, 1H),7.30-7.20 (m, 7H), 6.76-6.74 (m, 1H), 6.26 (d, J=15.5 Hz, 1H), 4.74-4.69(m, 1H), 4.20-4.11 (m, 2H), 3.45 (s, 2H), 3.32-3.23 (m, 2H), 2.90 (br s,2H), 2.19 (s, 3H), 2.15-2.11 (m, 2H), 1.89-1.78 (m, 2H), 1.56-1.42 (m,2H). MS: exact mass calculated for C₃₁H₃₂N₄O₄, 524.24; m/z found, 525.3[M+H]⁺, 547.2 [M+Na]⁺.

Example 34

trans-N-(1-Acetyl-2,3-dihydro-1H-indol-6-yl)-N-(1-benzyl-piperidin-4-yl)-3-(3-cyano-phenyl)-acrylamide

The title compound (68.4 mg, 72%) was prepared as in Example 20 usingtrans-3-(3-cyano-phenyl)-acrylic acid in place oftrans-3-thiophen-3-yl-acrylic acid. ¹H NMR (500 MHz, CDCl₃): 8.05 (s,1H), 7.58 (d, J=15.5 Hz, 1H), 7.53-7.48 (m, 3H), 7.40-7.37 (m, 1H),7.28-7.20 (m, 6H), 6.75-6.73 (m, 1H), 6.20 (d, J=15.5 Hz, 1H), 4.73-4.69(m, 1H), 4.23-4.13 (m, 2H), 3.45 (s, 2H), 3.37-3.26 (m, 2H), 2.89 (br s,2H), 2.25 (s, 3H), 2.15-2.10 (m, 2H), 1.88-1.77 (m, 2H), 1.55-1.44 (m,2H). MS: exact mass calculated for C₃₂H₃₂N₄O₂, 504.25; m/z found, 505.2[M+H]⁺, 527.2 [M+Na]⁺.

Example 35

trans-N-(1-Acetyl-2,3-dihydro-1H-indol-6-yl)-N-(1-benzyl-piperidin-4-yl)-3-(3-trifluoromethanesulfinyl-phenyl)-acrylamide

The title compound (66 mg, 55%) was prepared as in Example 18 using3-(3-trifluoromethanesulfinyl-phenyl)-propenal in place of3-phenyl-propenal. ¹H NMR (500 MHz, CDCl₃): 8.05 (s, 1H), 7.65-7.62 (m,3H), 7.53-7.48 (m, 2H), 7.28-7.18 (m, 6H), 6.74 (d, J=7.4 Hz, 1H), 6.23(d, J=15.0 Hz, 1H), 4.74-4.69 (m, 1H), 4.18-4.13 (m, 2H), 3.45 (s, 2H),3.30-3.24 (m, 2H), 2.94-2.84 (m, 2H), 2.23 (s, 3H), 2.13 (t, J=10.4 Hz,2H), 1.89-1.86 (m, 1H), 1.79-1.77 (m, 1H), 1.58-1.52 (m, 1H), 1.48-1.43(m, 1H). MS: exact mass calculated for C₃₂H₃₂F₃N₃O₃S, 595.21; m/z found,596.2 [M+H].

Example 36

trans-N-(1-Acetyl-2,3-dihydro-1H-indol-6-yl)-N-(1-benzyl-piperidin-4-yl)-3-(3,5-difluoro-phenyl)-acrylamide

The title compound (151 mg, 100%) was prepared as in Example 20 usingtrans-3-(3,5-difluoro-phenyl)-acrylic acid in place oftrans-3-thiophen-3-yl-acrylic acid. ¹H NMR (500 MHz, CDCl₃): 8.04 (s,1H), 7.51 (d, J=15.5 Hz, 1H), 7.33-7.23 (m, 6H), 6.77-6.68 (m, 4H), 6.14(d, J=15.5 Hz, 1H), 4.73-4.68 (m, 1H), 4.20-4.14 (m, 2H), 3.44 (s, 2H),3.32-3.25 (m, 2H), 2.91-2.87 (m, 2H), 2.24 (s, 3H), 2.15-2.10 (m, 2H),1.88-1.76 (m, 2H), 1.55-1.42 (m, 2H). MS: exact mass calculated forC₃₁H₃₁F₂N₃O₂, 515.24; m/z found, 516.3 [M+H]⁺, 538.3 [M+Na]⁺.

Example 37

trans-N-(1-Acetyl-2,3-dihydro-1H-indol-6-yl)-N-(1-benzyl-piperidin-4-yl)-3-(3,5-dimethyl-phenyl)-acrylamide

The title compound (67 mg, 70%) was prepared as in Example 20 usingtrans-3-(3,5-dimethyl-phenyl)-acrylic acid in place oftrans-3-thiophen-3-yl-acrylic acid. ¹H NMR (500 MHz, CDCl₃): 8.05 (s,1H), 7.57 (d, J=15.5 Hz, 1H), 7.28-7.16 (m, 6H), 6.89-6.88 (m, 3H),6.74-6.73 (m, 1H), 6.10 (d, J=15.5 Hz, 1H), 4.76-4.71 (m, 1H), 4.17-4.11(m, 2H), 3.44 (s, 2H), 3.28-3.23 (m, 2H), 2.88 (br s, 2H), 2.24 (s, 9H),2.15-2.10 (m, 2H), 1.90-1.75 (m, 2H), 1.56-1.40 (m, 2H).

MS: exact mass calculated for C₃₃H₃₇N₃O₂, 507.29; m/z found, 508.3[M+H]⁺, 530.2 [M+Na]⁺.

Example 38

trans-N-(1-Acetyl-2,3-dihydro-1H-indol-6-yl)-N-(1-benzyl-piperidin-4-yl)-3-(3,5-dichloro-phenyl)-acrylamide

The title compound (68.3 mg, 65%) was prepared as in Example 20 usingtrans-3-(3,5-dichloro-phenyl)-acrylic acid in place oftrans-3-thiophen-3-yl-acrylic acid. ¹H NMR (500 MHz, CDCl₃): 8.04 (s,1H), 7.48 (d, J=15.5 Hz, 1H), 7.28-7.19 (m, 7H), 7.12 (s, 2H), 6.73-6.72(m, 1H), 6.14 (d, J=15.5 Hz, 1H), 4.72-4.67 (m, 1H), 4.21-4.14 (m, 2H),3.44 (s, 2H), 3.32-3.25 (m, 2H), 2.91-2.87 (m, 2H), 2.24 (s, 3H),2.14-2.10 (m, 2H), 1.88-1.75 (m, 2H), 1.55-1.42 (m, 2H). MS: exact masscalculated for C₃₁H₃₁Cl₂N₃O₂, 547.18; m/z found, 548.2 [M+H]⁺, 550.2[M+H]⁺, 570.2 [M+Na]⁺.

Example 39

trans-N-(1-Acetyl-2,3-dihydro-1H-indol-6-yl)-N-(1-benzoyl-piperidin-4-yl)-3-phenyl-acrylamideStep A.1-[6-(1-Benzoyl-piperidin-4-ylamino)-2,3-dihydro-indol-1-yl]-ethanone

To a solution of 1-benzoyl-4-piperidone (250 mg, 1.2 mmol) and1-acetyl-6-aminoindoline (220 mg, 1.2 mmol), in CH₂Cl₂ (0.2 M) was addedAcOH (73 μL, 1.2 mmol), followed by Na(OAc)₃BH (390 mg, 1.8 mmol). Theresulting solution was allowed to stir overnight. The reaction wasquenched by the addition of satd. aq. NaHCO₃ and CH₂Cl₂. The layers wereseparated, and the organic portion was washed with brine, dried withNa₂SO₄ and concentrated. Purification by silica gel chromatography (1 to5% MeOH/CH₂Cl₂) provided the desired intermediate (132 mg, 30%).

Step B

The product from Step A (93 mg, 0.26 mmol) was acylated as in Example 2,Step C to provide the title compound (43 mg, 34%). ¹H NMR (500 MHz,CDCl₃): 8.09-7.98 (br m, 1H), 7.63 (d, J=15.5 Hz, 1H), 7.49-7.03 (m,11H), 6.80-6.61 (br m, 1H), 6.14 (d, J=15.5 Hz, 1H), 5.01-4.90 (m, 1H),4.83-4.68 (br m, 1H), 3.85-3.72 (br m, 1H), 3.22-3.08 (br m, 2H),2.92-2.78 (br m, 1H), 2.05-1.78 (br m, 3H), 1.51-1.29 (br m, 3H). MS:exact mass calculated for C₃₁H₃₁N₃O₃, 493.24; m/z found, 494.2 [M+H]⁺.

Example 40

trans-N-(1-Acetyl-2,3-dihydro-1H-indol-6-yl)-N-(1-phenethyl-piperidin-4-yl)-3-phenyl-acrylamideStep A.1-[6-(1-Phenethyl-piperidin-4-ylamino)-2,3-dihydro-indol-1-yl]-ethanone

The desired compound (133 mg, 64%) was prepared as in Example 39, StepA, employing 1-phenethylpiperidone in place of 1-benzoyl-4-piperidoneand using 1,2-dichloroethane as the solvent. ¹H NMR (500 MHz, CDCl₃):7.64 (d, J=1.4 Hz, 1H), 7.31-7.20 (m, 2H), 7.20-7.15 (m, 3H), 6.94 (d,J=7.9 Hz, 1H), 6.27 (dd, J=8.2, 1.8 Hz, 1H), 4.06-3.95 (m, 2H),3.39-3.29 (m, 1H), 3.10-3.02 (m, 2H), 2.97-2.90 (m, 2H), 2.84-2.77 (m,2H), 2.63-2.57 (m, 2H), 2.20 (s, 3H), 2.25-2.18 (m, 2H), 2.12-2.02 (m,2H), 1.55-1.40 (m, 2H).

MS: exact mass calculated for C₂₃H₂₉N₃O, 363.23; m/z found, 364.2[M+H]⁺.

Step B

The title compound (45 mg, 67%) was prepared from the product of Step A(50 mg, 0.1 mmol) as in Example 2, Step C. ¹H NMR (500 MHz, CDCl₃): 8.65(s, 1H), 7.63 (d, J=15.5 Hz, 1H), 7.30-7.22 (m, 7H), 7.20-7.12 (m, 4H),6.76 (dd, J=8.2, 1.4 Hz, 1H), 6.18 (d, J=15.5 Hz, 1H), 4.80-4.70 (m,1H), 4.14 (dd, J=16.8, 8.0 Hz, 2H), 3.31-3.19 (m, 2H), 3.07-2.95 (m,2H), 2.78-2.60 (m, 2H), 2.58-2.50 (m, 2H), 2.23 (s, 3H), 2.21-2.15 (m,2H), 1.98-1.81 (m, 2H), 1.65-1.46 (m, 2H). MS: exact mass calculated forC₃₂H₃₅N₃O₂, 493.27; m/z found, 494.2 [M+H]⁺.

Example 41

trans-N-(1-Acetyl-2,3-dihydro-1H-indol-6-yl)-3-phenyl-N-[1-(3-phenyl-propyl)-piperidin-4-yl]-acrylamideStep A.4-(1-Acetyl-2,3-dihydro-1H-indol-6-ylamino)-piperidine-1-carboxylic acidtert-butyl ester

The desired ester (2.37 g, 68%) was prepared as in Example 39, using4-oxo-piperidine-1-carboxylic acid tert-butyl ester (3.9 g, 19 mmol),1-acetyl-6-aminoindoline (1.7 g, 9.8 mmol), Na(OAc)₃BH (6.2 g, 29 mmol)and AcOH (3 mL, 50 mmol) in 1,2-dichloroethane (50 mL).

Step B.trans-4-[(1-Acetyl-2,3-dihydro-1H-indol-6-yl)-(3-phenyl-acryloyl)-amino]-piperidine-1-carboxylicacid tert-butyl ester

The title compound (2.26 g, 70%) was made from the product of Step A, asdescribed in Example 2, Step C. ¹H NMR (500 MHz, CDCl₃): 8.04 (s, 1H),7.64 (d, J=15.5 Hz, 1H), 7.36-7.21 (m, 5H), 7.19 (d, J=7.7 Hz, 1H), 6.74(dd, J=8.4, 1.3 Hz, 1H), 6.15 (d, J=15.5 Hz, 1H), 4.90-4.80 (m, 1H),4.21-3.98 (m, 4H), 3.33-3.21 (m, 2H), 2.90-2.75 (m, 2H), 2.24 (s, 3H),1.96-1.72 (m, 2H), 1.49-1.31 (m, 2H), 1.40 (s, 9H).

MS: exact mass calculated for C₂₉H₃₅N₃O₄, 489.26; m/z found, 512.3[M+Na]⁺.

Step C.trans-N-(1-Acetyl-2,3-dihydro-1H-indol-6-yl)-3-phenyl-N-piperidin-4-yl-acrylamide

The product from Step B (100 mg, 0.2 mmol) was dissolved in 2 mL ofCH₂Cl₂ and then TFA (2 mL) was added. After stirring for 1 h, thereaction mixture was concentrated under reduced pressure to provide thedesired product (80 mg, 69%). ¹H NMR (500 MHz, CDCl₃): 9.20-9.14 (m,1H), 8.61-8.49 (m, 1H), 8.00 (s, 1H), 7.64 (d, J=15.5 Hz, 1H), 7.32-7.27(m, 5H), 7.23 (d, J=7.8 Hz, 1H), 7.67 (d, J=6.7 Hz, 1H), 6.17 (d, J=15.5Hz, 1H), 4.97-4.85 (m, 1H), 4.21-4.15 (m, 2H), 3.54-3.35 (m, 2H),3.21-3.16 (m, 2H), 3.07-2.93 (m, 2H), 2.24 (s, 3H), 2.16-1.95 (m, 2H),1.82-162 (m, 2H). MS: exact mass calculated for C₂₄H₂₇N₃O₂, 389.21; m/zfound, 390.3 [M+H]⁺.

Step D

To a solution of 4-phenyl-butyraldehyde (104 mg, 0.780 mmol) and theacrylamide from Step C (232 mg, 0.60 mmol) in CH₂Cl₂ (0.2 M) was addedNa(OAc)₃BH (160 mg, 0.78 mmol). The resulting mixture was allowed tostir overnight. The reaction was quenched by the addition of satd. aq.NaHCO₃ and CH₂Cl₂. The layers were separated, and the organic portionwas extracted with brine, dried with Na₂SO₄, and concentrated.Purification by silica gel chromatography (1 to 5% MeOH/CH₂Cl₂) provided77 mg (25%) of the desired product. ¹H NMR (500 MHz, CDCl₃): 7.93 (d,J=1.8 Hz, 1H), 7.56 (d, J=15.4 Hz, 1H), 7.25-7.10 (m, 10H), 7.07 (dd,J=8.3, 1.5 Hz, 1H), 6.68 (dd, J=7.8, 2.0 Hz, 1H), 6.10 (d, J=15.6 Hz,1H), 4.83-4.68 (m, 1H), 4.15-4.02 (m, 2H), 3.25-3.15 (m, 2H), 2.62-2.53(m, 4H), 2.16 (s, 3H), 2.08-1.81 (m, 10H). MS: exact mass calculated forC₃₃H₃₇N₃O₂, 507.29; m/z found, 508.4 [M+H]⁺.

Example 42

trans-N-(1-Acetyl-2,3-dihydro-1H-indol-6-yl)-N-(1-cyclohexylmethyl-piperidin-4-yl)-3-phenyl-acrylamide

The title compound (238 mg, 50%) was prepared as in Example 41, Step D,employing cyclohexane-carboxaldehyde in place of 4-phenylbutyraldehyde.¹H NMR (500 MHz, CDCl₃): 7.91 (s, 1H), 7.52 (d, J=15.4 Hz, 1H),7.21-7.12 (m, 5H), 7.09 (d, J=8.1 Hz, 1H), 6.64 (dd, J=7.8, 2.0 Hz, 1H),6.06 (d, J=15.6 Hz, 1H), 4.80-4.50 (m, 1H), 4.04 (t, J=8.6 Hz, 2H),3.19-2.84 (m, 4H), 2.32-2.01 (m, 3H), 1.88 (s, 3H), 1.83-1.70 (m, 2H),1.69-1.44 (m, 8H), 1.18-0.93 (m, 4H), 0.89-0.62 (m, 2H). MS: exact masscalculated for C₃₁H₃₉N₃O₂, 485.30; m/z found, 486.4 [M+H]⁺.

Example 43

trans-N-(1-Acetyl-2,3-dihydro-1H-indol-6-yl)-N-[1-(2-cyclohexyl-ethyl)-piperidin-4-yl]-3-phenyl-acrylamide

The title compound (67 mg, 54%) was prepared as in Example 41, Step D,employing cyclohexyl-acetaldehyde in place of 4-phenylbutyraldehyde. ¹HNMR (500 MHz, CDCl₃): 7.97 (s, 1H), 7.56 (d, J=15.4 Hz, 1H), 7.25-7.15(m, 5H), 7.10 (d, J=8.3 Hz, 1H), 6.68 (dd, J=7.8, 1.5 Hz, 1H), 6.10 (d,J=15.7 Hz, 1H), 4.78-4.58 (br m, 1H), 4.13-3.98 (m, 2H), 3.28-3.08 (m,2H), 2.98-2.80 (m, 2H), 2.35-2.19 (m, 2H), 2.16 (s, 3H), 2.10-1.91 (m,3H), 1.87-1.69 (m, 2H), 1.64-1.49 (m, 5H), 1.33-1.20 (m, 2H), 1.99-0.98(m, 5H), 0.90-0.71 (m, 2H).

MS: exact mass calculated for C₃₂H₄₁N₃O₂, 499.32; m/z found, 500.4[M+H]⁺.

Example 44

trans-N-(1-Acetyl-2,3-dihydro-1H-indol-6-yl)-N-[1-(2-cyclopentyl-ethyl)-piperidin-4-yl]-3-phenyl-acrylamide

The title compound (53 mg, 37%) was prepared as in Example 41, Step D,employing cyclopentyl-acetaldehyde in place of 4-phenylbutyraldehyde. ¹HNMR (500 MHz, CDCl₃): 7.90-7.85 (br m, 1H), 7.56 (d, J=15.6 Hz, 1H),6.69 (br d, J=7.9 Hz, 1H), 6.10 (d, J=15.9 Hz, 1H), 4.74-4.66 (br m,1H), 4.11-4.04 (br m, 2H), 3.23-3.14 (m, 2H), 3.10-2.91 (m, 2H), 2.16(s, 3H), 1.91-1.70 (m, 4H), 1.71-1.61 (m, 3H), 1.62-1.29 (m, 8H),1.14-0.97 (m, 4H). MS: exact mass calculated for C₃₁H₃₉N₃O₂, 485.30; m/zfound, 486.5 [M+H]⁺.

Example 45

trans-N-(1-Acetyl-2,3-dihydro-1H-indol-6-yl)-N-(1-benzyl-piperidin-3-yl)-3-phenyl-acrylamideStep A.1-[6-(1-Benzyl-piperidin-3-ylamino)-2,3-dihydro-indol-1-yl]-ethanone

The desired intermediate (116 mg, 30%) was prepared as in Example 39,Step A, employing 1-benzyl-3-piperidone (510 mg, 4.4 mmol),1-acetyl-6-aminoindoline (200 mg, 1 mmol), Na(OAc)₃BH (910 mg, 4.3mmol), and AcOH (340 μL, 5.4 mmol) in 1,2-dichloroethane (20 mL).

Step B

The above intermediate (0.10 g, 0.29 mmol) was then reacted withcinnamoyl chloride (62 mg, 0.37 mmol) as in Example 2, Step C to provide145 mg (99%) of the desired product. ¹H NMR (500 MHz, CDCl₃): 8.04 (s,1H), 7.62 (d, J=15.5 Hz, 1H), 7.30-7.18 (m, 10H), 7.15 (d, J=7.8 Hz,1H), 6.74 (dd, J=7.3, 1.4 Hz, 1H), 6.16 (d, J=15.5 Hz, 1H), 4.79-4.68(m, 1H), 4.18-4.07 (m, 2H), 3.30-3.15 (m, 2H), 2.98-2.85 (m, 2H),2.26-2.23 (m, 2H), 2.21 (s, 3H), 2.15-2.01 (m, 2H), 1.93-1.75 (m, 2H),1.60-1.35 (m, 3H). MS: exact mass calculated for C₃₁H₃₃N₃O₂, 479.26; m/zfound, 480.2 [M+H]⁺.

Example 46

trans-N-(1-Acetyl-2,3-dihydro-1H-indol-6-yl)-N-(1-benzyl-pyrrolidin-3-yl)-3-phenyl-acrylamideStep A.1-[6-(1-benzyl-pyrrolidin-3-ylamino)-2,3-dihydro-indol-1-yl]-ethanone

The desired intermediate (84 mg, 44%) was prepared as in Example 39,Step A, using 1-benzyl-3-pyrrolidinone (0.20 g, 1.1 mmol),1-acetyl-6-aminoindoline (0.10 g, 0.57 mmol), Na(OAc)₃BH (360 mg, 1.7mmol), and AcOH (171 μL, 3.0 mmol) in 1,2-dichloroethane (10 mL). ¹H NMR(500 MHz, CDCl₃): 7.61 (s, 1H), 7.35-7.28 (m, 4H), 7.28-7.20 (m, 1H),6.93 (d, J=8.1 Hz, 1H), 6.24 (dd, J=8.2, 1.9 Hz, 1H), 4.05-3.96 (m, 3H),3.68-3.56 (m, 2H), 3.10-3.01 (m, 2H), 2.80-2.71 (m, 2H), 2.59-2.51 (m,1H), 2.48-2.39 (m, 1H), 2.38-2.22 (m, 1H), 2.20 (s, 3H), 1.71-1.56 (m,1H). MS: exact mass calculated for C₂₁H₂₅N₃O, 335.20; m/z found, 336.1[M+H]⁺.

Step B

The above intermediate (49 mg, 0.29 mmol) was reacted with cinnamoylchloride (276 mg, 0.2 mmol) as in Example 2, Step C to provide 79 mg(74%) of the desired product. ¹H NMR (500 MHz, CDCl₃): 8.09 (s, 1H),7.62 (d, J=15.5 Hz, 1H), 7.30-7.15 (m, 1H), 6.78 (d, J=7.0 Hz, 1H), 6.17(d, J=15.5 Hz, 1H), 5.15-5.05 (br m, 1H), 4.19-4.08 (m, 2H), 3.70-3.51(m, 2H), 3.29-3.20 (m, 2H), 3.07-2.95 (br m, 1H), 2.76-2.57 (br m, 3H),2.30-2.22 (m, 1H), 2.21 (s, 3H), 1.98-1.83 (m, 1H). MS: exact masscalculated for C₃₀H₃₁N₃O₂, 465.24; m/z found, 466.2 [M+H]⁺.

Example 47

trans-N-(1-Acetyl-2,3-dihydro-1H-indol-6-yl)-N-(3-benzylamino-propyl)-3-phenyl-acrylamideStep A. [3-(1-Acetyl-2,3-dihydro-1H-indol-6-ylamino)-propyl]-carbamicacid tert-butyl ester

A mixture of 1-(6-amino-2,3-dihydro-indol-1-yl)-ethanone (837 mg, 4.8mmol), (3-bromo-propyl)-carbamic acid tert-butyl ester (1.1 g, 4.8 mmol)and K₂CO₃ (1.3 g, 9.5 mmol) in acetonitrile (15 mL) was heated at refluxfor 48 h. A white precipitate was filtered off and the filtrate wasconcentrated under reduced pressure. The residue was purified on silicagel (50% EtOAc/hexanes) to give the desired product as a white solid(320 mg, 20%).

Step B.trans-{3-[(1-Acetyl-2,3-dihydro-1H-indol-6-yl)-(3-phenyl-acryloyl)-amino]-propyl}-carbamicacid tert-butyl ester

The ester from Step A (270 mg, 0.80 mmol) was acylated with cinnamoylchloride (203 mg, 1.2 mmol) as in Example 2, Step C to provide thedesired ester (345 mg, 92%).

Step C.trans-N-(1-acetyl-2,3-dihydro-1H-indol-6-yl)-N-(3-amino-propyl)-3-phenyl-acrylamide

The ester from Step B (345 mg, 0.7 mmol) was dissolved in CH₂Cl₂ (5.0mL) and was treated with TFA (2.5 mL). After 3 h, the reaction mixturewas concentrated. The resulting salt was diluted with EtOAc and treatedwith 1 N NaOH until pH 10 was achieved. The organic layer was thenseparated and concentrated under reduced pressure to give the desiredamine (268 mg, 100%), which was used without further purification.

Step D.trans-N-(1-Acetyl-2,3-dihydro-1H-indol-6-yl)-N-(3-benzylamino-propyl)-3-phenyl-acrylamide

The primary amine from Step C (268 mg, 0.74 mmol) and benzaldehyde (0.08mL, 0.74 mmol) were dissolved in MeOH and the resulting reaction mixturewas stirred at rt for 20 h. Sodium borohydride (45 mg, 1.2 mmol) wasadded. After 10 min, the reaction mixture was quenched with 1 N NaOH andthen extracted with EtOAc. The organic layer was concentrated underreduced pressure. The crude product was purified on silica gel (EtOAc)to give the title compound (235 mg, 70%). ¹H NMR (500 MHz, CDCl₃): 8.14(s, 1H), 7.65 (d, J=15.5 Hz, 1H), 7.31-7.29 (m, 5H), 7.27-7.26 (m, 5H),7.17 (d, J=7.9 Hz, 1H), 6.78 (d, J=7.1 Hz, 1H), 6.32 (d, J=15.5 Hz, 1H),4.15 (t, J=8.4 Hz, 2H), 3.91 (br s, 2H), 3.76 (s, 2H), 3.25 (t, J=8.5Hz, 2H), 2.66 (t, J=6.9 Hz, 2H), 2.24 (s, 3H), 1.80-1.74 (m, 2H). MS:exact mass calculated for C₂₉H₃₁N₃O₂, 453.24; m/z found, 454.2 [M+H]⁺.

Example 48

trans-N-(1-Acetyl-2,3-dihydro-1H-indol-6-yl)-N-[3-(allyl-benzyl-amino)-propyl]-3-phenyl-acrylamide

A mixture oftrans-N-(1-acetyl-2,3-dihydro-1H-indol-6-yl)-N-(3-benzylamino-propyl)-3-phenyl-acrylamide(Example 47, 39 mg, 0.090 mmol), allyl iodide (0.01 mL, 0.1 mmol), anddiisopropylethylamine (0.03 mL, 0.2 mmol) in CH₂Cl₂ (3.0 mL) was stirredat rt for 20 h. The reaction mixture was concentrated under reducedpressure and the crude product was purified on silica gel (60%EtOAc/hexanes) to provide the title compound (37 mg, 87%). ¹H NMR (500MHz, CDCl₃): 8.13 (s, 1H), 7.65 (d, J=15.5 Hz, 1H), 7.31-7.24 (m, 10H),7.15 (d, J=7.6 Hz, 1H), 6.71 (d, J=7.3 Hz, 1H), 6.30 (d, J=16.5 Hz, 1H),5.84-5.80 (m, 1H), 5.10 (dd, J=17.0, 10.1 Hz, 2H), 4.11 (t, J=7.3 Hz,2H), 3.84 (br s, 2H), 3.50 (s, 2H), 3.24 (t, J=8.5 Hz, 2H), 3.02 (d,J=6.3 Hz, 2H), 2.46 (t, J=7.1 Hz, 2H), 2.23 (s, 3H), 1.81-1.75 (m, 2H).MS: exact mass calculated for C₃₂H₃₅N₃O₂, 493.64; m/z found, 494.2[M+H]⁺.

Example 49

trans-N-(1-Acetyl-2,3-dihydro-1H-indol-6-yl)-3-(4-chloro-phenyl)-N-[1-(2-cyclohexyl-ethyl)-piperidin-4-yl]-acrylamideStep A.trans-4-{(1-Acetyl-2,3-dihydro-1H-indol-6-yl)-[3-(4-chloro-phenyl)-acryloyl]-amino}-piperidine-1-carboxylicacid tert-butyl ester

The ester (1.26 g, 87%) was prepared as in Example 20 usingtrans-3-(4-chloro-phenyl)-acrylic acid in place oftrans-3-thiophen-3-yl-acrylic acid and4-(1-acetyl-2,3-dihydro-1H-indol-6-ylamino)-piperidine-1-carboxylic acidtert-butyl ester (Example 41, Step A) in place of1-[6-(1-benzyl-piperidin-4-ylamino)-2,3-dihydro-indol-1-yl]-ethanone. ¹HNMR (500 MHz, CDCl₃): 8.02 (s, 1H), 7.56 (d, J=15.5 Hz, 1H), 7.21-7.17(m, 5H), 6.73-6.71 (m, 1H), 6.10 (d, J=15.5 Hz, 1H), 4.84-4.79 (m, 1H),4.17-4.12 (m, 4H), 3.29-3.24 (m, 2H), 2.80 (br s, 2H), 2.23 (s, 3H),1.90-1.77 (m, 2H), 1.51-1.27 (m, 11H). MS: exact mass calculated forC₂₉H₃₄ClN₃O₄, 523.22; m/z found, 546.2 [M+Na]⁺, 548.2 [M+Na]⁺.

Step B.trans-N-(1-Acetyl-2,3-dihydro-1H-indol-6-yl)-3-(4-chloro-phenyl)-N-piperidin-4-yl-acrylamide

The intermediate from Step A (1.22 g, 2.32 mmol) was dissolved in CH₂Cl₂(10 mL) and was treated with TFA (10 mL). The mixture was stirred for 30min at rt and then was concentrated in vacuo. The residue was dissolvedin CH₂Cl₂ and treated with Dowex 550A resin. After stirring for severalhours, the mixture was filtered and concentrated in vacuo to give 966 mg(98%) of the desired compound, which was taken on to the next stepwithout further purification.

Step C

The title compound (54 mg, 61%) was prepared from the intermediate fromStep B (70.0 mg, 0.165 mmol) as in Example 43, using 1,2-dichloroethaneas the solvent. ¹H NMR (500 MHz, CDCl₃): 8.04 (s, 1H), 7.57 (d, J=15.5Hz, 1H), 7.30-7.16 (m, 5H), 6.75 (br s, 1H), 6.14 (d, J=15.5 Hz, 1H),4.75 (br s, 1H), 4.17-4.14 (m, 2H) 3.53-3.27 (m, 4H), 2.92 (br s, 2H),2.28-2.23 (m, 4H), 2.07-2.04 (m, 2H), 1.66-1.43 (m, 9H), 1.29-1.11 (m,5H), 0.89-0.86 (m, 2H).

MS: exact mass calculated for C₃₂H₄₀ClN₃O₂, 533.28; m/z found, 534.2[M+H]⁺, 556.3 [M+Na]⁺.

Example 50

trans-N-(1-Acetyl-2,3-dihydro-1H-indol-6-yl)-N-[1-(2-cyclohexyl-ethyl)-piperidin-4-yl]-3-(3-nitro-phenyl)-acrylamide

The title compound (54 mg, 62%) was prepared as in Example 49, usingtrans-3-(3-nitro-phenyl)-acrylic acid in place oftrans-3-(4-chloro-phenyl)-acrylic acid.

¹H NMR (500 MHz, CDCl₃): 8.10-8.05 (m, 3H), 7.66 (d, J=15.5 Hz, 1H),7.59-7.57 (m, 1H), 7.46-7.43 (m, 1H), 7.21-7.19 (m, 1H), 6.77-6.75 (m,1H), 6.28 (d, J=15.5 Hz, 1H), 4.75-4.70 (m, 1H), 4.19-4.13 (m, 2H),3.31-3.20 (m, 3H), 2.98 (br s, 2H), 2.33 (br s, 2H), 2.23 (s, 3H), 2.10(br s, 2H), 1.89-1.86 (m, 2H), 1.70-1.55 (m, 6H), 1.32-1.10 (m, 6H),0.91-0.84 (m, 2H). MS: exact mass calculated for C₃₂H₄₀N₄O₄, 544.30; m/zfound, 545.3 [M+H]⁺, 567.3 [M+Na]⁺.

Example 51

trans-N-(1-Acetyl-2,3-dihydro-1H-indol-6-yl)-3-(4-chloro-phenyl)-N-[1-(2-cyclopentyl-ethyl)-piperidin-4-yl]-acrylamide

The title compound (72 mg, 60%) was prepared as in Example 49, usingcyclopentyl-acetaldehyde in place of cyclohexyl-acetaldehyde. ¹H NMR(500 MHz, CDCl₃): 8.04 (s, 1H), 7.57 (d, J=15.5 Hz, 1H), 7.23-7.16 (m,5H), 6.75-6.73 (m, 1H), 6.14 (d, J=15.5 Hz, 1H), 4.75-4.70 (m, 1H),4.17-4.10 (m, 2H), 3.32-3.22 (m, 2H), 2.98-2.96 (m, 2H), 2.39-2.18 (m,7H), 2.16-2.09 (m, 2H), 1.92-1.40 (m, 11H), 1.07-1.05 (m, 2H). MS: exactmass calculated for C₃₁H₃₈ClN₃O₂, 519.27; m/z found, 520.2 [M+H]⁺, 522.2[M+H]⁺, 543.2 [M+Na]⁺.

Example 52

trans-N-(1-Acetyl-2,3-dihydro-1H-indol-6-yl)-N-[1-(2-cyclopentyl-ethyl)-piperidin-4-yl]-3-(3-nitro-phenyl)-acrylamide

The title compound (67.1 mg, 55%) was prepared as in Example 50, usingcyclopentyl-acetaldehyde in place of cyclohexyl-acetaldehyde. ¹H NMR(500 MHz, CDCl₃): 8.10-8.07 (m, 3H), 7.66 (d, J=15.5 Hz, 1H), 7.59-7.57(m, 1H), 7.46-7.43 (m, 1H), 7.20-7.19 (m, 1H), 6.77-6.75 (m, 1H), 6.28(d, J=15.5 Hz, 1H), 4.74-4.71 (m, 1H), 4.19-4.10 (m, 2H), 3.31-3.23 (m,2H), 2.96-2.94 (m, 2H), 2.31-2.18 (m, 5H), 2.07-2.04 (m, 2H), 1.78-1.44(m, 13H), 1.07-1.04 (m, 2H). MS: exact mass calculated for C₃₁H₃₈N₄O₄,530.29; m/z found, 531.3 [M+H]⁺, 553.3 [M+Na]⁺.

Example 53

trans-N-(1-Acetyl-2,3-dihydro-1H-indol-6-yl)-3-(3-cyano-phenyl)-N-[1-(2-cyclopentyl-ethyl)-piperidin-4-yl]-acrylamide

The title compound (61 mg, 50%) was prepared as in Example 52, usingtrans-3-(3-cyano-phenyl)-acrylic acid in place oftrans-3-(4-chloro-phenyl)-acrylic acid. ¹H NMR (500 MHz, CDCl₃): 8.04(s, 1H), 7.59 (d, J=15.5 Hz, 1H), 7.53-7.49 (m, 3H), 7.40-7.37 (m, 1H),7.20-7.19 (m, 1H), 6.78-6.73 (m, 1H), 6.22 (d, J=15.5 Hz, 1H), 4.72 (brs, 1H), 4.22-4.11 (m, 2H), 3.34-3.24 (m, 2H), 2.96 (br s, 1H), 2.30-2.24(m, 5H), 2.08-1.86 (m, 6H), 1.71-1.44 (m, 10H), 1.07-1.03 (m, 2H). MS:exact mass calculated for C₃₂H₃₈N₄O₂, 510.30; m/z found, 511.2 [M+H]⁺,533.3 [M+Na]⁺.

Example 54

trans-N-(1-Acetyl-2,3-dihydro-1H-indol-6-yl)-N-(1-benzyl-piperidin-4-yl)-3-(4-chloro-phenyl)-acrylamide

The title compound (135 mg, 92%) was prepared as in Example 20 usingtrans-3-(4-chloro-phenyl)-acrylic acid in place oftrans-3-thiophen-3-yl-acrylic acid.

¹H NMR (500 MHz, CDCl₃): 8.04 (s, 1H), 7.56 (d, J=15.5 Hz, 1H),7.31-7.15 (m, 10H), 6.73 (dd, J=8.1, 1.5 Hz, 1H), 6.12 (d, J=15.5 Hz,1H), 4.75-4.68 (m, 1H), 4.18-4.12 (m, 2H), 3.44 (s, 2H), 3.31-3.22 (m,2H), 2.91-2.86 (m, 2H), 2.23 (s, 3H), 2.18-2.05 (m, 2H), 1.90-1.70 (m,2H), 1.60-1.51 (m, 1H), 1.50-1.37 (m, 1H). MS: exact mass calculated forC₃₁H₃₂ClN₃O₂, 513.22; m/z found, 514.2 [M+H]⁺.

Example 55

trans-{4-[(1-Acetyl-2,3-dihydro-1H-indol-6-yl)-(3-phenyl-acryloyl)-amino]-piperidin-1-yl}-phenyl-aceticacid methyl ester

To a solution oftrans-N-(1-acetyl-2,3-dihydro-1H-indol-6-yl)-3-phenyl-N-piperidin-4-yl-acrylamide(Example 41, Step C; 49 mg, 0.13 mmol) in DMF (0.5 mL) and DCM (2 mL)was added Na₂CO₃ (41 mg, 0.39 mmol) followed by methylα-bromophenylacetate (26 μL, 0.16 mmol). After stirring overnight, thereaction mixture was poured into H₂O and DCM was added. The organicfraction was washed with brine (3×), dried (Na₂SO₄), and concentrated.Purification by silica gel chromatography (2% methanol (2 M NH₃) in DCM)afforded 59 mg (84%) of the title compound. ¹H NMR (400 MHz, CDCl₃):8.04 (br d, J=12.4 Hz, 1H), 7.62 (d, J=15.4 Hz, 1H), 7.38-7.22 (m, 10H),7.18 (dd, J=8.8, 8.0 Hz, 1H), 6.73 (dd, J=17.2, 7.8 Hz, 1H), 6.15 (d,J=15.6 Hz, 1H), 4.74 (br dd, J=12.4, 12.1 Hz, 1H), 4.17 (dd, J=8.8, 8.3Hz, 2H), 3.94 (d, J=3.8 Hz, 1H), 3.65 (s, 3H), 3.31-3.24 (m, 2H),3.01-2.94 (m, 1H), 2.76-2.69 (m, 1H), 2.34-2.22 (m, 1H), 2.24 (d, J=5.3Hz, 3H), 2.02-1.76 (m, 2H), 1.76-1.63 (m, 1H), 1.61 (s, 3H), 1.58-1.40(m, 1H). MS: exact mass calculated for C₃₃H₃₅N₃O₄, 537.3; m/z found,538.5 [M+H]⁺.

Example 56

trans-N-(1-Acetyl-2,3-dihydro-1H-indol-6-yl)-N-[1-(ethylcarbamoyl-phenyl-methyl)-piperidin-4-yl]-3-phenyl-acrylamide

The title compound (x mg, x %) was prepared fromtrans-N-(1-acetyl-2,3-dihydro-1H-indol-6-yl)-3-phenyl-N-piperidin-4-yl-acrylamideand 2-bromo-N-ethyl-2-phenyl-acetamide as described in Example 55. Aftersilica gel chromatography, the compound was further purified byreverse-phase HPLC to yield the desired product as its TFA salt. ¹H NMR(400 MHz, CDCl₃): 8.58-8.48 (m, 1H), 8.06-7.91 (m, 1H), 7.57 (d, J=15.6Hz, 1H), 7.55-7.46 (m, 5H), 7.46-7.34 (m, 1H), 7.34-7.23 (m, 3H),7.00-6.85 (m, 1H), 6.22 (d, J=15.4 Hz, 1H), 4.47-4.67 (m, 1H), 4.30-4.18(m, 2H), 3.85-3.68 (m, 1H), 3.37-3.14 (m, 9H), 3.13-3.01 (m, 1H),2.99-2.84 (m, 1H), 2.25 (br s, 3H), 2.10-1.71 (m, 2H), 1.03 (t, J=7.3Hz, 3H). MS: exact mass calculated for C₃₄H₃₈N₄O₃, 550.3; m/z found,551.5 [M+H]⁺.

Assay Methods Radioligand Binding Assay

KAN-Ts endogenously expressing Y2 receptors were used for theradioligand binding assay. Cells were grown to confluence on 150 cm²tissue culture plates, washed with phosphate-buffered saline (PBS), andscraped into 50 mL tubes. After centrifugation, the supernatant wasaspirated, and the pellets frozen and stored at −80° C. Thawed pelletswere homogenized with a polytron tissue grinder for 15 sec in 20 mMTris-HCl, 5 mM EDTA. The homogenate was centrifuged at 800×g for 5 minand the collected supernatant was recentrifuged at 25000×g for 25 min.The resulting pellet was resuspended in binding buffer (20 mM HEPES, 120mM NaCl, 0.22 mM KH₂PO₄, 1.3 mM CaCl₂, 0.8 mM MgSO₄). Membranes wereincubated with [¹²⁵I]PYY (80 pM) in the presence or absence of testcompound for 1 h at rt. The reaction was stopped by filtration throughGF/C filter plates pre-soaked in 0.3% polyethylenimine and subsequentlywashed with Tris 50 mM, 5 mM EDTA buffer. Plates were dried for 1 h in a55° C. oven, scintillation fluid was added and the radioactivity wascounted in a Packard TopCount. Specific binding to the NPY receptorsubtypes was determined by radioactivity that was bound in the presenceof 1 mM NPY. Each binding experiment was repeated three to eight times,each in duplicate. IC₅₀ values (i.e. concentration of unlabelled peptideor antagonist required to compete for 50% of specific binding to theradioligand) were calculated using the GraphPad Prism software (GraphPadSoftware Inc., San Diego Calif.) with a fit to a sigmoidal dose responsecurve. Data were expressed as pIC₅₀ values where pIC₅₀=−log IC₅₀. Datais presented in Table 1.

TABLE 1 EX IC₅₀ (μM) 1 4.0 2 22 3 3.5 4 4.8 5 4.8 6 5.3 7 15 8 30 9 1010 30 11 30 12 18 13 11 14 30 15 30 16 9.2 17 22 18 2.8 19 30 20 3.2 2130 22 30 23 12 24 30 25 17 26 2.8 27 8.9 28 30 29 3.3 30 3.6 31 3.0 321.4 33 1.9 34 1.0 35 5.8 36 2.5 37 3.9 38 30 39 29 40 26 41 2.3 42 1.143 0.6 44 0.8 45 16 46 18 47 12 48 12 49 1.1 50 0.5 51 1.1 52 0.35 530.1 54 3.6 55 6.3 56 30[³⁵S] GTPγS binding assay in KAN-Ts cells

Membranes from KAN-Ts cells were prepared as described above. Membraneswere thawed on ice and diluted in 50 mM Tris-HCl buffer, pH 7.4containing 10 mM MgCl₂, 1 mM EDTA, 100 mM NaCl, 5 mM GDP, 0.25% BSA.Assay mixtures (150 mL) were preincubated with compounds for 30 min atrt. Then, 50 mL of [³⁵S]GTPγS in assay buffer was added to a finalconcentration of 200 μM and the assay mixtures were incubated for 1 h atrt. Reactions were terminated by rapid filtration thought GF/C filters.Filters were washes twice with ice cold 50 mM Tris-HCl, pH 7.4containing 10 mM MgCl₂. Basal [³⁵S]GTPγS was measured in the absence ofcompounds. In initial experiments, nonspecific binding was measured inthe presence of 100 mM GTPγS. This nonspecific binding never exceeded10% of basal binding and was thus not subtracted from experimental data.Stimulation of [³⁵S]GTPγS is presented as percentage over basal and wascalculated as one hundred times the difference between stimulated andbasal binding (in cpm). Agonist concentration-response curves forincreases in [³⁵S]GTPγS binding and antagonist inhibition curves forinhibition of PYY (300 nM)-stimulated [³⁵S]GTPγS binding were analyzedby non-linear regression using GraphPad Prism software (GraphPadSoftware Inc., San Diego Calif.). EC₅₀ (concentration of compound atwhich 50% of its own maximal stimulation is obtained) and IC₅₀(concentration of its own maximal inhibition of PYY-stimulated[³⁵S]GTPγS binding is obtained) were derived from the curves. IC₅₀values were corrected as follows: corrected IC₅₀(IC₅₀corr)=IC₅₀/(1+[PYY]/EC₅₀ (PYY)) and pIC₅₀corr=−log IC₅₀corr. Thetitle compound of Example 53 was demonstrated to be a competitive inthis assay (pIC₅₀=7.20).

1-10. (canceled)
 11. A method for the treatment or prevention of diseasestates mediated by NPY Y2 receptor activity comprising the step ofadministering to a mammal suffering there from a therapeuticallyeffective amount of compound having NPY Y2 receptor activity of formula(I):

wherein the fused pyrrolidine ring optionally contains a singlecarbon-carbon double bond or a single carbon ring member adjacent to thenitrogen is optionally ═O substituted; n is 1 or 2; m is 0, 1, or 2; Y₁is a C₀₋₅ alkylene, C₀₋₅ alkenylene, C₀₋₅ alkynylene, C₀₋₅acylene;—CH(CONR^(f)R^(g))— (where R^(f) and R^(g) are independently H orC₁₋₄alkyl), or —CH(CO₂C₁₋₄alkyl)-; Y₂ is H, phenyl, C₄₋₈ cycloalkyl orC₄₋₈ cycloalkenyl, each ring optionally substituted with R^(q); Y₃ is—CH₂—, carbonyl or sulfone; Y₄ is a substituted or unsubstituted C₂₋₇alkyl, C₂₋₇ alkenyl, C₂₋₇ alkynyl or C₃₋₇cycloalkyl; Y₅ is phenyl,furanyl, thiophenyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, dioxolanyl,oxazolyl, thiazolyl, imidazolyl, imidazolidinyl, pyrazolyl, pyrazolinyl,pyrazolidinyl, oxadiazolyl, triazolyl, thiadiazolyl, pyranyl, pyridyl,piperidinyl, dioxanyl, morpholinyl, dithianyl, thiomorpholinyl,pyridazinyl, pyrimidinyl, pyrazinyl, piperazinyl, naphthalenyl,quinolonyl, purinyl, indolyl, benzofuranyl, or benzothiophenyl, eachoptionally mono-, di- or tri-substituted with R_(q); R₁ is H or is

where R_(a) is H, a substituted or unsubstituted C₁₋₅ alkyl, C₁₋₅alkenyl, C₁₋₅ alkynyl or C₁₋₅ acyl, where the substituent is C₁₋₄alkoxyor one or more fluoro; R₂ and R₃ are independently selected from H, asubstituted or unsubstituted C₁₋₅ alkyl, C₁₋₅ alkenyl, or C₁₋₅ alkynyl,or R₂ and R₃ may be taken together with the nitrogen of R₃ attachment toform piperidine or pyrrolidine or azepanyl; and R^(q) is selected fromthe group consisting of —OH, —C₁₋₆ alkyl, —OC₁₋₆ alkyl, Ph-, —OPh,benzyl, —Obenzyl, —C₃₋₆ cycloalkyl, —OC₃₋₆ cycloalkyl, —CN, —NO₂,—N(R_(y))R_(z) (wherein R_(y) and R_(z) are independently selected fromH, C₁₋₆ alkyl, C₁₋₆ alkenyl, or R_(y) and R_(z) may be taken togetherwith the nitrogen of attachment to form an otherwise aliphatichydrocarbon ring, said ring having 4 to 7 members, optionally having onecarbon replaced with 0, ═N—, NH or N(C₁₋₄alkyl), optionally having onecarbon substituted with —OH, and optionally having one or twounsaturated bonds in the ring), —(C═O)N(R_(y))R_(z), —(N—R^(t))COR^(t),—(N—R_(t))SO₂C₁₋₆alkyl (wherein R^(t) is H or C₁₋₆alkyl or two R_(t) inthe same substituent may be taken together with the amide of attachmentto form an otherwise aliphatic hydrocarbon ring, said ring having 4 to 6members), —(C═O)C₁₋₆alkyl, —(S═(O)_(n))—C₁₋₆alkyl (wherein n is selectedfrom 0, 1 or 2), —SO₂N(R_(y))R_(z), —SCF₃, halo, —CF₃, —OCF₃, —COOH and—COOC₁₋₆ alkyl; and enantiomers, diastereomers, hydrates, solvates andpharmaceutically acceptable salts, esters and amides thereof.
 12. Amethod of claim 11 for treatment of an anxiolytic disorder or depressioncomprising administering to a subject suffering there from atherapeutically effective amount of a compound of claim 1 orenantiomers, diastereomers, hydrates, solvates and pharmaceuticallyacceptable salts, esters and amides thereof.
 13. A method of claim 11for treatment of injured mammalian nerve tissue comprising administeringto a subject suffering there from a therapeutically effective amount ofa compound of claim 1 or enantiomers, diastereomers, hydrates, solvatesand pharmaceutically acceptable salts, esters and amides thereof.
 14. Amethod of claim 11 comprising administering to a subject suffering froma condition amenable to treatment through administration of aneurotrophic factor a therapeutically effective amount of a compound ofclaim 1 or enantiomers, diastereomers, hydrates, solvates andpharmaceutically acceptable salts, esters and amides thereof.
 15. Amethod of claim 11 for treatment of a neurological disorder comprisingadministering to a subject suffering there from a therapeuticallyeffective amount of a compound of claim 1 or enantiomers, diastereomers,hydrates, solvates and pharmaceutically acceptable salts, esters andamides thereof.
 16. A method of claim 11 for treatment of bone losscomprising administering to a subject suffering there from atherapeutically effective amount of a compound of claim 1 orenantiomers, diastereomers, hydrates, solvates and pharmaceuticallyacceptable salts, esters and amides thereof.
 17. A method of claim 11for treatment of obesity or an obesity-related disorder comprisingadministering to a subject suffering there from a therapeuticallyeffective amount of a compound of claim 1 or enantiomers, diastereomers,hydrates, solvates and pharmaceutically acceptable salts, esters andamides thereof.
 18. A method of claim 11 for treatment of infertilitycomprising administering to an infertile subject a therapeuticallyeffective amount of a compound of claim 1 or enantiomers, diastereomers,hydrates, solvates and pharmaceutically acceptable salts, esters andamides thereof.
 19. A method of claim 11 for treatment of an endocrinedisorder comprising administering to a subject suffering there from atherapeutically effective amount of a compound of claim 1 orenantiomers, diastereomers, hydrates, solvates and pharmaceuticallyacceptable salts, esters and amides thereof.
 20. A method of claim 11for treatment of substance related disorders comprising administering toa subject suffering there from a therapeutically effective amount of acompound of claim 1 or enantiomers, diastereomers, hydrates, solvatesand pharmaceutically acceptable salts, esters and amides thereof.